Pyrimidine-based compounds for the treatment of cancer

ABSTRACT

This invention is in the area of pyrimidine-based compounds for the treatment of disorders involving abnormal cellular proliferation, including but not limited to tumors and cancers.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of International Application No.PCT/US2017/040097, filed with the Patent Cooperation Treaty, U.S.Receiving Office on Jun. 29, 2017, which claims the benefit of U.S.Provisional Application 62/357,818 which was filed on Jul. 1, 2016. Theentirety of these applications are hereby incorporated by referenceherein for all purposes.

FIELD OF THE INVENTION

This invention is in the area of pyrimidine-based compounds for thetreatment of disorders involving abnormal cellular proliferation,including but not limited to tumors and cancers.

BACKGROUND

In normal tissue, cellular proliferation is generally restricted tocells that are required to replenish the tissue. Once cells haveterminally differentiated, they have a specialized function and nolonger divide. Most tissues are made up of non-dividing cells. Thus,normal cell proliferation is tightly controlled to ensure that only thenecessary cells divide. There is also a careful balance between celldivision and programmed cell death (apoptosis).

Cell division, sometimes referred to as the cell cycle, has four phases:G₁ phase (synthesis of various enzymes required for DNA replication), Sphase (DNA replication producing two identical sets of chromosomes), G₂(significant protein synthesis, including production of microtubules)and M phase (nuclear division, cytoplasmic division and formation of newcell membrane). Cell division also includes a complex system of cellsignaling networks that allow cells to interpret information fromnumerous extracellular signals, including through receptor proteins,inflammatory factors and pro-apoptotic and anti-apoptotic signals.Dysfunctional signals include those from genetic mutation, infection,exposure to environmental factors including toxins, system stress,autoimmune disorders, and inflammation.

A range of disorders can occur when the process of cell proliferationbecomes dysfunctional, including benign growths, neoplasms,tumorigenesis, cancerogenesis, autoimmune disorders, inflammatorydisorders graft-versus-host rejection, and fibrotic disorders.

A number of broad-spectrum anti-neoplastic agents have been developed.Cytoskeletal drugs like paclitaxel target tubulin to arrest mitotic celldivision and are used to treat a variety of cancers including ovarian,breast, lung, pancreatic, and testicular tumors (See e.g., Jordan,Wilson, Nature Reviews Cancer (2004) 4: 253-265). Organometallic-baseddrugs such as cisplatin have been used to treat lymphomas, sarcomas,germ cell tumors, and some carcinomas including bladder, small cell lungcancer, and ovarian cancer. Cisplatin has the ability to bindnitrogenous bases and cause extensive DNA cross-linking that ultimatelyleads to apoptosis (See e.g., Siddick, Oncogene (2003) 22: 7265-7279).Intercalating and alkylating agents have also been extensive use in theclinic for the treatment of various neoplasms, however, the globaltoxicity associated with these drugs presents a critical concern forpatients requiring long-term therapy.

Palbociclib (PD-033299; Ibrance) is sold by Pfizer for the treatment ofestrogen-positive, HER2-negative breast cancer in combination withletrozole. The compound inhibits CDK4 and CDK6. The structure ofpalbociclib is:

Abemaciclib (LY2835219) is a CDK 4/6 inhibitor currently in humanclinical trials for the treatment of various types of cancers. It is ina phase III trial for stage IV non-small cell lung carcinoma; incombination with Fulvestrant for women with breast cancer; and witheither anastrozole or letrozole for first line treatment of breastcancer. The structure of abemaciclib is:

Ribociclib (Lee011; Kisqali), is a CDK 4/6 inhibitor approved for use incombination with an aromatase inhibitor to treat some metastatic breastcancers, and is in clinical trials for the treatment of certain othertumors. The structure of ribociclib is:

Various other pyrimidine-based agents have been developed for thetreatment of hyperproliferative diseases. U.S. Pat. Nos. 8,822,683;8,598,197; 8,598,186; 8,691,830; 8,829,102; 8,822,683; 9,102,682;9,499,564; 9,481,591; and 9,260,442, filed by Tavares and Strum andassigned to G1 Therapeutics describe a class ofN-(heteroaryl)-pyrrolo[3,2-d]pyrimidin-2-amine cyclin dependent kinaseinhibitors including those of the formula (with variables as definedtherein):

U.S. Pat. Nos. 9,464,092, 9,487,530, and 9,527,857 which are alsoassigned to G1 Therapeutics describe the use of the abovepyrimidine-based agents in the treatment of cancer.

WO 2013/148748 (U.S. Ser. No. 61/617,657) titled “Lactam KinaseInhibitors”, WO 2013/163239 (U.S. Ser. No. 61/638,491) titled “Synthesisof Lactams” and WO 2015/061407 filed by Tavares and also assigned to G1Therapeutics describes the synthesis ofN-(heteroaryl)-pyrrolo[3,2-d]pyrimidin-2-amines and their use as lactamkinase inhibitors.

Other publications include the following. WO 2014/144326 filed by Strumet al. and assigned to G1 Therapeutics describes compounds and methodsfor protection of normal cells during chemotherapy usingpyrimidine-based CDK4/6 inhibitors. WO 2014/144596 filed by Strum et al.and assigned to G1 Therapeutics describes compounds and methods forprotection of hematopoietic stem and progenitor cells against ionizingradiation using pyrimidine-based CDK4/6 inhibitors. WO 2014/144847 filedby Strum et al. and assigned to G1 Therapeutics describes HSPC-sparingtreatments of abnormal cellular proliferation using pyrimidine-basedCDK4/6 inhibitors. WO 2014/144740 filed by Strum et al. and assigned toG1 Therapeutics describes highly active anti-neoplastic andanti-proliferative pyrimidine-based CDK 4/6 inhibitors. WO 2015/161285filed by Strum et al. and assigned to G1 Therapeutics describestricyclic pyrimidine-based CDK inhibitors for use in radioprotection. WO2015/161287 filed by Strum et al. and assigned to G1 Therapeuticsdescribes analogous tricyclic pyrimidine-based CDK inhibitors for theprotection of cells during chemotherapy. WO 2015/161283 filed by Strumet al. and assigned to G1 Therapeutics describes analogous tricyclicpyrimidine-based CDK inhibitors for use in HSPC-sparing treatments ofRB-positive abnormal cellular proliferation. WO 2015/161288 filed byStrum et al. and assigned to G1 Therapeutics describes analogoustricyclic pyrimidine-based CDK inhibitors for use as anti-neoplastic andanti-proliferative agents. WO 2016/040858 filed by Strum et al. andassigned to G1 Therapeutics describes the use of combinations ofpyrimidine-based CDK4/6 inhibitors with other anti-neoplastic agents. WO2016/040848 filed by Strum et al. and assigned to G1 Therapeuticsdescribes compounds and methods for treating certain Rb-negative cancerswith CDK4/6 inhibitors and topoisomerase inhibitors.

WO 03/062236 identifies a series of2-(pyridin-2-ylamino-pyrido[2,3]pyrimidin-7-ones for the treatment of Rbpositive cancers that show selectivity for CDK4/6, including6-acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-1-yl-pyridin-2-ylammino)-8H-pyrido-[2,3-d]-pyrimidin-7-one(PD0332991), which was given fast-track approval by the FDA and iscurrently sold as Ibrance (Palbociclib) by Pfizer for the treatment ofmetastatic breast cancer.

VanderWel et al. describe an iodine-containingpyrido[2,3-d]pyrimidine-7-one (CKIA) as a potent and selective CDK4inhibitor (see VanderWel et al., J. Med. Chem. 48 (2005) 2371-2387).

WO 2010/020675 filed by Novartis AG describes pyrrolopyrimidinecompounds as CDK inhibitors. WO 2011/101409 also filed by Novartisdescribes pyrrolopyrimidines with CDK 4/6 inhibitory activity.

Johnson et al. reported that pharmacological inhibition of CDK4/6 usingthe CDK4/6 inhibitors6-acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-1-yl-pyridin-2-ylammino)-8H-pyrido-[2,3-d]-pyrimidin-7-one(PD0332991) and2-bromo-12,13-dihydro-5H-indolo[2,3-a]pyrrolo[3,4]carbazole-5,6-dione(2BrIC) exhibited IR protective characteristics in CDK4/6-dependent celllines. (Johnson et al. Mitigation of hematological radiation toxicity inmice through pharmacological quiescence induced by CDK4/6 inhibition. JClin. Invest. 2010; 120(7): 2528-2536).

There remains a need for additional compounds to treat disordersassociated with abnormal cellular proliferation, including a tumor orcancer.

SUMMARY

Compounds are provided that have advantageous antiproliferativeactivity, including anticancer and antitumor activity. Based on thisdiscovery, compounds and methods are presented for the treatment of apatient with a proliferative disorder including a tumor or cancer thatincludes administering an effective amount of one or a combination ofthe compounds described herein to a patient in need thereof, optionallyin a pharmaceutically acceptable carrier. In certain embodiments, theantiproliferative disorder is selected from a benign growth, neoplasm,tumor, cancer, autoimmune disorder, inflammatory disorder,graft-versus-host rejection and a fibrotic disorder. In a typicalembodiment, the patient is a human.

The invention includes an active compound of Formula I, Formula II,Formula III, and Formula IV or a pharmaceutically acceptable salt orcomposition thereof. In one embodiment, an active compound or its salt,composition, or prodrug thereof is used to treat a medical disorderinvolving abnormal cellular proliferation.

In one aspect of the present invention a compound of Formula I, FormulaII, Formula III, or Formula IV is provided:

or a pharmaceutically acceptable salt, N-oxide, isotopic derivative,prodrug, and/or a pharmaceutically acceptable composition thereof;wherein:

y is 0, 1, 2, 3 or 4;

Z is S, CH₂, CHR¹², CR¹²R¹³, NH, or NR¹²;

represents the presence or absence of a double bond;

R is hydrogen, C₁-C₆alkyl, —(C₀-C₂alkyl)(C₃-C₈carbocyclyl),—(C₀-C₂alkyl)(C₃-C₈heterocyclyl), —(C₀-C₂alkyl)(aryl),—(C₀-C₂alkyl)heteroaryl), —COOalkyl, —COOarylalkyl, or —COOH;

each R¹ is independently alkyl, aryl, cycloalkyl or haloalkyl, whereineach of said alkyl, cycloalkyl and haloalkyl groups optionally includesheteroatoms O, N, or S in place of a carbon in the chain and two R¹'s onadjacent ring atoms or on the same ring atom together with the ringatom(s) to which they are attached optionally form a 3-8-membered cycleor two R¹'s on adjacent ring atoms together with the ring atom(s) towhich they are attached optionally form a 6-membered aryl ring;

the 3-8 membered cycle formed by combining two R¹s with the atom(s) towhich they are attached can be either a carbocycle or a heterocycle;

in an alternative embodiment, the 3-8 membered cycle formed by combiningtwo R's with the atom(s) to which they are attached can be optionallysubstituted with one or more substituents selected from amino, —NHR¹⁴,—NR¹⁴R¹⁵, hydroxyl, OR¹⁴, R⁶, and R²;

R⁷ is selected from:

or R⁷ is selected from cycloalkyl, heterocycle, and alkyl, each of whichcycloalkyl, heterocycle, and alkyl groups is optionally substituted withone or more substituents selected from amino, —NHR¹⁴, —NR¹⁴R¹⁵,hydroxyl, OR¹⁴, R⁶, and R²;

Y is NH, O, S, or NR⁹;

X¹, X², X³, X⁴, and X⁵ are independently N or CR⁸, wherein at least oneof X¹, X², X³, X⁴, and X⁵ are CR⁸;

R⁸ is selected independently at each instance from: R⁶ and R², whereinone R⁸ is R²;

R² is independently selected from -(alkylene)_(m)-heterocyclo,-(alkylene)_(m)-heteroaryl, -(alkylene)_(m)-NR³R⁴,-(alkylene)_(m)-C(O)—NR³R⁴; -(alkylene)_(m)-C(O)—O-alkyl;-(alkylene)_(m)-O—R⁵, -(alkylene)_(m)-S(O)_(n)—R⁵, or-(alkylene)_(m)-S(O)_(n)—NR³R⁴ any of which may be optionallyindependently substituted with one or more R^(x) groups as allowed byvalance, and wherein two R^(x) groups bound to the same or adjacent atommay optionally combine to form a ring;

m is 0 or 1;

n is 0, 1 or 2;

R³ and R⁴ at each occurrence are independently selected from:

-   -   (i) hydrogen or    -   (ii) alkyl, cycloalkyl, heterocyclo, aryl, heteroaryl,        cycloalkylalkyl, heterocycloalkyl, arylalkyl, or heteroarylalkyl        any of which may be optionally independently substituted with        one or more R^(x) groups as allowed by valance, and wherein two        R^(x) groups bound to the same or adjacent atom may optionally        combine to form a ring; or R³ and R⁴ together with the nitrogen        atom to which they are attached may combine to form a        heterocyclo ring optionally independently substituted with one        or more R^(x) groups as allowed by valance, and wherein two        R^(x) groups bound to the same or adjacent atom may optionally        combine to form a ring;

R⁵ is independently selected at each occurrence from:

(i) hydrogen or

(ii) alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl,cycloalkylalkyl, heterocycloalkyl, arylalkyl, or heteroarylalkyl any ofwhich may be optionally independently substituted with one or more R^(x)groups as allowed by valance;

R^(x) at each occurrence is independently selected from halo, cyano,nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo,aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl,heterocycloalkyl, -(alkylene)_(m)-OR⁵, -(alkylene)_(m)-O-alkylene-OR⁵,-(alkylene)_(m)-S(O)_(n)—R⁵, -(alkylene)_(m)-NR³R⁴, -(alkylene)_(m)-CN,-(alkylene)_(m)-C(O)—R⁵, -(alkylene)_(m)-C(S)—R⁵,-(alkylene)_(m)-C(O)—OR⁵, -(alkylene)_(m)-O—C(O)—R⁵,-(alkylene)_(m)-C(S)—OR⁵, -(alkylene)_(m)-C(O)-(alkylene)_(m)-NR³R⁴,-(alkylene)_(m)-C(S)—NR³R⁴, -(alkylene)_(m)-N(R³)—C(O)—NR³R⁴,-(alkylene)_(m)-N(R³)—C(S)—NR³R⁴, -(alkylene)_(m)-N(R³)—C(O)—R⁵,-(alkylene)_(m)-N(R³)—C(S)—R⁵, -(alkylene)_(m)-O—C(O)—NR³R⁴,-(alkylene)_(m)-O—C(S)—NR³R⁴, -(alkylene)_(m)-SO₂—NR³R⁴,-(alkylene)_(m)-N(R³)—SO₂—R⁵, -(alkylene)_(m)-N(R³)—SO₂—NR³R⁴,-(alkylene)_(m)-N(R³)—C(O)—OR⁵)-(alkylene)_(m)-N(R³)—C(S)—OR⁵, or-(alkylene)_(m)-N(R³)—SO₂—R⁵, wherein: said alkyl, haloalkyl, alkenyl,alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl groups may befurther independently substituted as described herein;

R⁶ is selected independently at each instance from: hydrogen, halogen,alkyl, alkenyl, alkynyl cycloalkyl, heterocyclo, aryl, heteroaryl,cycloalkylalkyl, heterocycloalkyl, arylalkyl, or heteroarylalkyl;

R⁹ is selected from: —C(O)H, —C(O)alkyl, —C(S)alkyl, alkyl, aryl,heteroaryl, arylalkyl, and heteroarylalkyl;

R¹⁰ and R¹¹ are selected from: hydrogen, alkyl, —NH₂, —NHR¹², —NR¹²R¹³,—S(O)alkyl, and —SO₂alkyl;

or R¹⁰ and R¹¹ are selected from: cycloalkyl, heterocycle, aryl,heteroaryl, arylalkyl, and heteroarylalkyl, each of which is optionallysubstituted with one or more substituents selected from amino, —NHR¹⁴,—NR¹⁴R¹⁵, hydroxyl, OR¹⁴, R⁶, and R²;

R¹² is selected from: hydrogen, alkyl, alkenyl, alkynyl, —C(O)H,—C(O)alkyl, —C(S)alkyl, aryl, —SO₂alkyl, heteroaryl, arylalkyl, andheteroarylalkyl;

or R¹² is selected from cycloalkyl, heterocycle, aryl, heteroaryl,arylalkyl, and heteroarylalkyl, each of which is optionally substitutedwith one or more substituents selected from amino, —NHR¹⁴, —NR¹⁴R¹⁵,hydroxyl, OR¹⁴, R⁶, and R²;

R¹³ is independently selected from: hydrogen, alkyl, alkenyl, alkynyl,—C(O)H, —C(O)alkyl, —C(S)alkyl, aryl, —SO₂alkyl, heteroaryl, arylalkyl,and heteroarylalkyl;

or R¹³ is selected from cycloalkyl, heterocycle, aryl, heteroaryl,arylalkyl, and heteroarylalkyl, each of which is optionally substitutedwith one or more substituents selected from amino, —NHR¹⁴, —NR¹⁴R¹⁵,hydroxyl, OR¹⁴, R⁶, and R²; and

R¹⁴ and R¹⁵ are independently selected from: hydrogen, alkyl, alkenyl,alkynyl, —C(O)H, —C(O)alkyl, —C(S)alkyl, aryl, —SO₂alkyl, heteroaryl,arylalkyl, and heteroarylalkyl.

These compounds can be used to treat such condition in a host in needthereof, typically a human.

In one embodiment, the active compound acts as an inhibitor of acyclin-dependent kinase (CDK), for example CDK4 and/or CDK6. In oneaspect, the compound is a selective inhibitor of CDK4 and/or CDK6. Inanother embodiment, the selectivity is for CDK4 and/or CDK6 over CDK2.Based on this, in one embodiment, the method for the treatment of adisorder of abnormal cellular proliferation that is mediated by CDK4 andor CDK6 is provided that includes the administration of an effectiveamount of a compound of the present invention or a pharmaceuticallyacceptable salt thereof, optionally in a pharmaceutically acceptablecarrier, as described in more detail below.

In an alternative embodiment, a method for the treatment of a disorderof abnormal cellular proliferation that is not mediated by CDK4 and orCDK6 is provided that includes the administration of an effective amountof a compound of the present invention or a pharmaceutically acceptablesalt thereof, optionally in a pharmaceutically acceptable carrier, asdescribed in more detail below.

In another embodiment, a method for the treatment of a fibrotic disorderin a host is provided that includes the administration of an effectiveamount of a compound of the present invention or a pharmaceuticallyacceptable salt thereof, optionally in a pharmaceutically acceptablecarrier.

In another embodiment, a method for the treatment of rheumatoidarthritis or psoriasis in a host is provided that includes theadministration of an effective amount of a compound of the presentinvention or a pharmaceutically acceptable salt thereof, optionally in apharmaceutically acceptable carrier.

In yet another embodiment, a method for the treatment of an autoimmunedisorder in a host is provided that includes the administration of aneffective amount of a compound of the present invention or apharmaceutically acceptable salt thereof, optionally in apharmaceutically acceptable carrier.

In a principal embodiment, a method for the treatment of a tumor orcancer in a host is provided that includes the administration of aneffective amount of a compound of the present invention or apharmaceutically acceptable salt thereof, optionally in apharmaceutically acceptable carrier. In an aspect of this embodiment,the cancer is an Rb-positive tumor or cancer. In another aspect of thisembodiment, the cancer is an Rb-negative tumor or cancer. In certainaspects, the cancer is selected from breast cancer, prostate cancer(including androgen-resistant prostate cancer), another cancer of thereproductive system such as endometrial, ovarian or testicular cancer,small cell lung carcinoma, glioblastoma and head and/or neck cancer.

In yet another embodiment, a method for the treatment of a disorder ofabnormal cellular proliferation in a host such as a human is providedthat includes administering an effective amount of a combination of oneor more of the active compounds described herein in combination oralternation with another active compound. In certain aspects of theinvention, the second compound is a chemotherapeutic agent. In anotheraspect of this embodiment, the second active compound is an immunemodulator, including but not limited to a checkpoint inhibitor such asan anti-PD1, anti-CTLA, anti-LAG-3, anti-Tim, etc. antibody, smallmolecule, peptide, nucleotide or other inhibitor (including but notlimited to ipilimumab (Yervoy), Pembrolizumab (Keytruda) and nivolumab(Opdivo).

In yet another embodiment, one of the active compounds described hereinis administered in an effective amount for the treatment of abnormaltissue of the female reproductive system such as breast, ovarian,endometrial, or uterine cancer, in combination or alternation with aneffective amount of an estrogen inhibitor including but not limited to aSERM (selective estrogen receptor modulator), a SERD (selective estrogenreceptor degrader), a complete estrogen receptor degrader, or anotherform of partial or complete estrogen antagonist.

In another embodiment, one of the active compounds described herein isadministered in an effective amount for the treatment of abnormal tissueof the male reproductive system such as prostate or testicular cancer,in combination or alternation with an effective amount of an androgen(such as testosterone) inhibitor including but not limited to aselective androgen receptor modulator, a selective androgen receptordegrader, a complete androgen receptor degrader, or another form ofpartial or complete androgen antagonist. In one embodiment, the prostateor testicular cancer is androgen-resistant.

In one embodiment, the compounds described herein inhibit CyclinDependent Kinase. For example, a compound described in the presentinvention provides a dose-dependent G1-arresting effect on a subject'sCDK replication dependent healthy cells, for example HSPCs or renalepithelial cells. The methods provided for herein are sufficient toafford chemoprotection to targeted CDK replication dependent healthycells during chemotherapeutic agent exposure, for example, during thetime period that a DNA-damaging chemotherapeutic agent is capable ofDNA-damaging effects on CDK replication dependent healthy cells in thesubject.

In one embodiment, the use of the compounds or methods described hereinis combined with the use of hematopoietic growth factors including, butnot limited to, granulocyte colony stimulating factor (G-CSF),granulocyte-macrophage colony stimulating factor (GM-CSF),thrombopoietin, interleukin (IL)-12, steel factor, and erythropoietin(EPO), or their derivatives. In one embodiment, the compound isadministered prior to administration of the hematopoietic growth factor.In one embodiment, the hematopoietic growth factor administration istimed so that the compound's effect on HSPCs has dissipated.

The present invention thus includes at least the following features:

(a) a compound of the present invention as described herein, andpharmaceutically acceptable salts and prodrugs thereof;

(b) a compound of the present invention as described herein, andpharmaceutically acceptable salts and prodrugs thereof that are usefulin the treatment of a disorder of abnormal cellular proliferation,including a tumor or cancer;

(c) use of a compound of the present invention, or pharmaceuticallyacceptable salts and prodrugs thereof in the manufacture of a medicamentfor the treatment of a disorder of abnormal cellular proliferation, suchas a tumor or cancer;

(d) a method for manufacturing a medicament intended for the therapeuticuse of treating a disorder of abnormal cellular proliferation includinga tumor or cancer, characterized in that a compound of the presentinvention as described herein is used in the manufacture;

(e) a compound of the present invention as described herein, andpharmaceutically acceptable salts and prodrugs thereof that are usefulin the treatment of cancer, including any of the cancers describedherein;

(f) use of a compound of the present invention, and pharmaceuticallyacceptable salts and prodrugs thereof in the manufacture of a medicamentfor the treatment of cancer, including any of the cancers describedherein;

(g) a method for manufacturing a medicament intended for the therapeuticuse of treating cancer, including any of the cancers described herein,characterized in that a compound of the present invention as describedherein is used in the manufacture;

(h) a compound of the present invention as described herein, andpharmaceutically acceptable salts and prodrugs thereof that are usefulin the treatment of a tumor, including any of the tumors describedherein;

(i) use of a compound of the present invention, and pharmaceuticallyacceptable salts and prodrugs thereof in the manufacture of a medicamentfor the treatment of a tumor, including any of the tumors describedherein;

(j) a method for manufacturing a medicament intended for the therapeuticuse of treating a tumor, including any of the tumors described herein,characterized in that a compound of the present invention as describedherein is used in the manufacture;

(k) a compound of the present invention as described herein, andpharmaceutically acceptable salts and prodrugs thereof that are usefulin the treatment of a fibrotic disorder;

(l) use of a compound of the present invention, and pharmaceuticallyacceptable salts and prodrugs thereof in the manufacture of a medicamentfor the treatment of a fibrotic disorder;

(m) a method for manufacturing a medicament intended for the therapeuticuse of treating a fibrotic disorder, characterized in that a compound ofthe present invention as described herein is used in the manufacture;

(n) a compound of the present invention as described herein, andpharmaceutically acceptable salts and prodrugs thereof that are usefulin the treatment of an autoimmune or inflammatory disorder;

(o) use of a compound of the present invention, and pharmaceuticallyacceptable salts and prodrugs thereof in the manufacture of a medicamentfor the treatment of an autoimmune or inflammatory disorder;

(p) a method for manufacturing a medicament intended for the therapeuticuse of treating an autoimmune or inflammatory disorder, characterized inthat a compound of the present invention as described herein is used inthe manufacture;

(q) a pharmaceutical formulation comprising an effective host-treatingamount of the compound of the present invention or a pharmaceuticallyacceptable salt or prodrug thereof together with a pharmaceuticallyacceptable carrier or diluent;

(r) a compound of the present invention as described herein as a mixtureof enantiomers or diastereomers (as relevant), including as a racemate;

(s) a compound of the present invention as described herein inenantiomerically or diastereomerically (as relevant) enriched form,including as an isolated enantiomer or diastereomer (i.e., greater than85, 90, 95, 97 or 99% pure); and,

(t) a process for the preparation of therapeutic products that containan effective amount of a compound of the present invention, as describedherein.

(u) a compound of the present invention as described herein, andpharmaceutically acceptable salts and prodrugs thereof that are usefulin chemoprotection;

(v) use of a compound of the present invention, and pharmaceuticallyacceptable salts and prodrugs thereof in the manufacture of a medicamentfor chemoprotection; and

(w) a method for manufacturing a medicament intended for the therapeuticuse of chemoprotection, characterized in that a compound of the presentinvention as described herein is used in the manufacture.

BRIEF DESCRIPTION OF FIGURES

FIG. 1 is a bar graph showing the population of cells with a DNA contentless than 2N, cells in the G0-G1 phase, cells in the S phase, and cellsin the G2-M phase as a way to measure the relative amount of apoptoticcells following administration of control, Compound 12, and Compound 13.Greater than 70% of the cells were apoptotic (the population of cellswith less than 2N) after exposure to Compound 12 and Compound 13. TheCompound number and dose, measured in μM and nM) are shown on the x-axisand the cell population, measured in percent, is shown on the y-axis.

FIG. 2 is a bar graph showing the population of cells with a DNA contentless than 2N, cells in the G0-G1 phase, cells in the S phase, and cellsin the G2-M phase as a way to measure the relative amount of apoptoticcells following administration of control and Compound 10. Thepopulation of apoptotic cells after exposure to Compound 10 ranged fromapproximately 70% to 90% depending on the dose. The Compound number anddose, measured in μM and nM) are shown on the x-axis and the cellpopulation, measured in percent, is shown on the y-axis.

FIG. 3 is Formula I, Formula II, Formula III, and Formula IV.

FIG. 4 is a bar graph showing the population of cells with a DNA contentless than 2N, cells in the G0-G1 phase, cells in the S phase, and cellsin the G2-M phase as a way to measure the relative amount of apoptoticcells following administration of control, Compound 1, and Compound 30.The population of apoptotic cells after exposure to Compound 30 wasgreater than 70% at every dose administered, while the population ofapoptotic cells after exposure to Compound 1 ranged from approximately50% to approximately 70% depending on the dose. The assay was done in apopulation of Hs68 cells. * is <2000 events. The Compound number anddose, measured in μM and nM, are shown on the x-axis and the cellpopulation, measured in percent, is shown on the y-axis.

DETAILED DESCRIPTION I. Compounds

In one embodiment, compounds of Formula I, Formula II, Formula III, orFormula IV are provided:

or a pharmaceutically acceptable salt, N-oxide, isotopic derivative,prodrug, and/or a pharmaceutically acceptable composition thereof;wherein the variables are as defined above in the Summary.

In one embodiment, a compound of Formula I-1, Formula II-1, FormulaIII-1, or Formula IV-1 is provided:

wherein:

y is 0, 1, 2, 3 or 4;

Z is S, CH₂, CHR¹², CR¹²R¹³, NH, or NR¹²;

represents the presence or absence of a double bond;

R is hydrogen, C₁-C₆alkyl, —(C₀-C₂alkyl)(C₃-C₈carbocyclyl),—(C₀-C₂alkyl)(C₃-C₈heterocyclyl), —(C₀-C₂alkyl)(aryl),—(C₀-C₂alkyl)heteroaryl), —COOalkyl, —COOarylalkyl, or —COOH;

each R¹ is independently alkyl, aryl, cycloalkyl or haloalkyl, whereineach of said alkyl, cycloalkyl and haloalkyl groups optionally includesheteroatoms O, N, or S in place of a carbon in the chain and two R¹'s onadjacent ring atoms or on the same ring atom together with the ringatom(s) to which they are attached optionally form a 3-8-membered cycleor two R¹'s on adjacent ring atoms together with the ring atom(s) towhich they are attached optionally form a 6-membered aryl ring;

the 3-8 membered cycle formed by combining two R¹s with the atom(s) towhich they are attached can be either a carbocycle or a heterocycle;

in an alternative embodiment, the 3-8 membered cycle formed by combiningtwo R¹s with the atom(s) to which they are attached can be optionallysubstituted with one or more substituents selected from amino, —NHR¹⁴,—NR¹⁴R¹⁵, hydroxyl, OR¹⁴, R⁶, and R²;

R⁷ is selected from:

or R⁷ is selected from cycloalkyl, heterocycle, and alkyl, each of whichcycloalkyl, heterocycle, and alkyl groups is optionally substituted withone or more substituents selected from amino, —NHR¹⁴, —NR¹⁴R¹⁵,hydroxyl, OR¹⁴, R⁶, and R²;

Y is NH, O, S, or NR⁹;

X¹, X², X³, X⁴, and X⁵ are independently N or CR⁸, wherein at least oneof X¹, X², X³, X⁴, and X⁵ are CR⁸;

R⁸ is selected independently at each instance from: R⁶ and R², whereinone R⁸ is R²;

R² is independently selected from -(alkylene)_(m)-heterocyclo,-(alkylene)_(m)-heteroaryl, -(alkylene)_(m)-NR³R⁴,-(alkylene)_(m)-C(O)—NR³R⁴; -(alkylene)_(m)-C(O)—O-alkyl;-(alkylene)_(m)-O—R⁵, -(alkylene)_(m)-S(O)_(n)—R⁵, or-(alkylene)_(m)-S(O)_(n)—NR³R⁴ any of which may be optionallyindependently substituted with one or more R^(x) groups as allowed byvalance, and wherein two R^(x) groups bound to the same or adjacent atommay optionally combine to form a ring;

m is 0 or 1;

n is 0, 1 or 2;

R³ and R⁴ at each occurrence are independently:

-   -   (i) hydrogen or    -   (ii) alkyl, cycloalkyl, heterocyclo, aryl, heteroaryl,        cycloalkylalkyl, heterocycloalkyl, arylalkyl, or        heteroarylalkyl; or R³ and R⁴ together with the nitrogen atom to        which they are attached may combine to form a heterocyclo ring;

R⁵ is independently:

(i) hydrogen or

(ii) alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl,cycloalkylalkyl, heterocycloalkyl, arylalkyl, or heteroarylalkyl;

R^(x) at each occurrence is independently selected from halo, cyano,nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo,aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl,heterocycloalkyl, -(alkylene)_(m)-OR⁵, -(alkylene)_(m)-O-alkylene-OR⁵,-(alkylene)_(m)-S(O)_(n)—R⁵, -(alkylene)_(m)-NR³R⁴, -(alkylene)_(m)-CN,-(alkylene)_(m)-C(O)—R⁵, -(alkylene)_(m)-C(S)—R⁵,-(alkylene)_(m)-C(O)—OR⁵, -(alkylene)_(m)-O—C(O)—R⁵,-(alkylene)_(m)-C(S)—OR⁵, -(alkylene)_(m)-C(O)-(alkylene)_(m)-NR³R⁴,-(alkylene)_(m)-C(S)—NR³R⁴, -(alkylene)_(m)-N(R³)—C(O)—NR³R⁴,-(alkylene)_(m)-N(R³)—C(S)—NR³R⁴, -(alkylene)_(m)-N(R³)—C(O)—R⁵,-(alkylene)_(m)-N(R³)—C(S)—R⁵, -(alkylene)_(m)-O—C(O)—NR³R⁴,-(alkylene)_(m)-O—C(S)—NR³R⁴, -(alkylene)_(m)-SO₂—NR³R⁴,-(alkylene)_(m)-N(R³)—SO₂—R⁵, -(alkylene)_(m)-N(R³)—SO₂—NR³R⁴,-(alkylene)_(m)-N(R³)—C(O)—OR⁵)-(alkylene)_(m)-N(R³)—C(S)—OR⁵, and-(alkylene)_(m)-N(R³)—SO₂—R;

R⁶ is selected independently at each instance from: hydrogen, halogen,alkyl, alkenyl, alkynyl cycloalkyl, heterocyclo, aryl, heteroaryl,cycloalkylalkyl, heterocycloalkyl, arylalkyl, or heteroarylalkyl;

R⁹ is selected from: —C(O)H, —C(O)alkyl, —C(S)alkyl, alkyl, aryl,heteroaryl, arylalkyl, and heteroarylalkyl;

R¹⁰ and R¹¹ are selected from: hydrogen, alkyl, —NH₂, —NHR¹², —NR¹²R¹³,—S(O)alkyl, and —SO₂alkyl;

or R¹⁰ and R¹¹ are selected from: cycloalkyl, heterocycle, aryl,heteroaryl, arylalkyl, and heteroarylalkyl, each of which is optionallysubstituted with one or more substituents selected from amino, —NHR¹⁴,—NR¹⁴R¹⁵, hydroxyl, OR¹⁴, R⁶, and R²;

R¹² is selected from: hydrogen, alkyl, alkenyl, alkynyl, —C(O)H,—C(O)alkyl, —C(S)alkyl, aryl, —SO₂alkyl, heteroaryl, arylalkyl, andheteroarylalkyl;

or R¹² is selected from cycloalkyl, heterocycle, aryl, heteroaryl,arylalkyl, and heteroarylalkyl, each of which is optionally substitutedwith one or more substituents selected from amino, —NHR¹⁴, —NR¹⁴R¹⁵,hydroxyl, OR¹⁴, R⁶, and R²;

R¹³ is independently selected from: hydrogen, alkyl, alkenyl, alkynyl,—C(O)H, —C(O)alkyl, —C(S)alkyl, aryl, —SO₂alkyl, heteroaryl, arylalkyl,and heteroarylalkyl;

or R¹³ is selected from cycloalkyl, heterocycle, aryl, heteroaryl,arylalkyl, and heteroarylalkyl, each of which is optionally substitutedwith one or more substituents selected from amino, —NHR¹⁴, —NR¹⁴R¹⁵,hydroxyl, OR¹⁴, R⁶, and R²; and

R¹⁴ and R¹⁵ are independently selected from: hydrogen, alkyl, alkenyl,alkynyl, —C(O)H, —C(O)alkyl, —C(S)alkyl, aryl, —SO₂alkyl, heteroaryl,arylalkyl, and heteroarylalkyl.

In an additional embodiment, R⁷ is selected from:

In an additional embodiment, R⁷ is selected from:

In some aspects, R⁶ is hydrogen.

In some aspects, R^(x) is not further substituted.

In some aspects, R² is -(alkylene)_(m)-heterocyclo,-(alkylene)_(m)-heteroaryl, -(alkylene)_(m)-NR³R⁴,-(alkylene)_(m)-C(O)—NR³R⁴; -(alkylene)_(m)-O—R⁵,-(alkylene)_(m)-S(O)_(n)—R⁵, or -(alkylene)_(m)-S(O)_(n)—NR³R⁴ any ofwhich may be optionally independently substituted with one or more R^(x)groups as allowed by valance, and wherein two R^(x) groups bound to thesame or adjacent atom may optionally combine to form a ring and whereinm is 0 or 1 and n is 0, 1 or 2.

In some aspects, R² is -(alkylene)_(m)-heterocyclo,-(alkylene)_(m)-NR³R⁴, -(alkylene)_(m)-C(O)—NR³R⁴,-(alkylene)_(m)-C(O)—O-alkyl or -(alkylene)_(m)-OR⁵ any of which may beoptionally independently substituted with one or more R^(x) groups asallowed by valance, and wherein two R^(x) groups bound to the same oradjacent atom may optionally combine to form a ring.

In some aspects, R² is -(alkylene)_(m)-heterocyclo,-(alkylene)_(m)-NR³R⁴, -(alkylene)_(m)-C(O)—NR³R⁴,-(alkylene)_(m)-C(O)—O-alkyl or -(alkylene)_(m)-OR⁵ without furthersubstitution.

In some aspects, m in R² is 1. In a further aspect, the alkylene in R²is methylene.

In some aspects, R² is

wherein:

R^(2*)is a bond, alkylene, -(alkylene)_(m)-O-(alkylene)_(m)-,-(alkylene)_(m)-C(O)-(alkylene)_(m)-,-(alkylene)_(m)-S(O)₂-(alkylene)_(m)- and-(alkylene)_(m)-NH-(alkylene)_(m)- wherein each m is independently 0 or1;

P is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group;

each R^(x1) is independently-(alkylene)_(m)-(C(O))_(m)-(alkylene)_(m)-(N(R^(N)))_(m)-(alkyl)_(m)wherein each m is independently 0 or 1 provided at least one m is 1,—(C(O))—O-alkyl, -(alkylene)_(m)-cycloalkyl wherein m is 0 or 1,—N(R^(N))-cycloalkyl, —C(O)-cycloalkyl, -(alkylene)_(m)-heterocyclylwherein m is 0 or 1, or —N(R^(N))-heterocyclyl, —C(O)-heterocyclyl,—S(O)₂-(alkylene)_(m) wherein m is 1 or 2, wherein:

-   -   R^(N) is H, C₁ to C₄ alkyl or C₁ to C₆ heteroalkyl, and    -   wherein two R^(x1) can, together with the atoms to which they        attach on P, which may be the same atom, form a ring; and    -   t is 0, 1 or 2.

In some aspects, each R^(x1) is only optionally substituted byunsubstituted alkyl, halogen or hydroxy.

In some aspects, R^(x1) is hydrogen or unsubstituted C₁-C₄ alkyl.

In some aspects, at least one R^(x1) is -(alkylene)_(m)-heterocyclylwherein m is 0 or 1.

In some aspects, R² is

wherein P* is a 4- to 8-membered mono- or bicyclic saturatedheterocyclyl group.

In some aspects, R² is

In some aspects, R² is

In some aspects, R² is

wherein:

R²* is a bond, alkylene, -(alkylene)_(m)-O-(alkylene)_(m)-,-(alkylene)_(m)-C(O)-(alkylene)_(m)-,-(alkylene)_(m)-S(O)₂-(alkylene)_(m)- and-(alkylene)_(m)-NH-(alkylene)_(m)- wherein each m is independently 0 or1;

P is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group;

P1 is a 4- to 6-membered monocyclic saturated heterocyclyl group;

each R^(x2) is independently hydrogen or alkyl; and

s is 0, 1 or 2.

In some aspects, R² is

In some aspects, P1 includes at least one nitrogen.

In some aspects, any alkylene in R²* in any previous aspect is notfurther substituted.

In some aspects, R² is

In one embodiment, a compound of Formula I-2, Formula II-2, FormulaIII-2, or Formula IV-2 is provided:

wherein R⁷, R¹⁰, and R¹¹ are as defined in Formula II-1, and FormulaIII-1 above.

In one embodiment, a compound of Formula I-3, Formula II-3, FormulaIII-3, or Formula IV-3 is provided:

wherein R¹, R², y, R¹⁰, and R¹¹ are as defined in Formula II-1, andFormula III-1 above.

In some aspects, the compound has general Formula Ia:

wherein R, R¹, R², X¹, X², X³ and y are as previously defined.

In some aspects, the compound has general Formula Ib:

wherein R, R¹, R², and y are as previously defined.

In some aspects, the compound has general Formula Ic:

wherein R and R², are as previously defined.

In some aspects, the compound has general Formula Id:

wherein R, R², X¹, and X² are as previously defined.

In some aspects, the compound has general Formula Ie:

wherein R, R², X¹, and X² are as previously defined.

In some aspects, the compound has general Formula If:

wherein R, R², X¹, X², and X³ are as previously defined.

In some aspects, the compound has general Formula IIa:

wherein R, R¹, R², R¹⁰, X¹, X² and y are as previously defined.

In some aspects, the compound has general Formula IIb:

wherein R, R¹, R², R¹⁰, and y are as previously defined.

In some aspects, the compound has general Formula IIc:

wherein R R¹⁰, and R², are as previously defined.

In some aspects, the compound has general Formula IId:

wherein R, R², R¹⁰, X¹, and X² are as previously defined.

In some aspects, the compound has general Formula IIe:

wherein R, R², R¹⁰, X¹, and X² are as previously defined.

In some aspects, the compound has general Formula IIf:

wherein R, R¹⁰, R², X¹, X², and X³ are as previously defined.

In some aspects, the compound has general Formula IIIa:

wherein R¹⁰, R², X¹, X², and y are as previously defined.

In some aspects, the compound has general Formula IIIb:

wherein R¹⁰, R¹, R², and y are as previously defined.

In some aspects, the compound has general Formula IIIc:

wherein R¹⁰ and R², are as previously defined.

In some aspects, the compound has general Formula IIId:

wherein R², R¹⁰, X¹, and X² are as previously defined.

In some aspects, the compound has general Formula IIIe:

wherein R², R¹⁰, X¹, and X² are as previously defined.

In some aspects, the compound has general Formula IIIf:

wherein R², R¹⁰, X¹, X², and X³ are as previously defined.

In some aspects, the compound has general Formula IVa:

wherein R, R¹, R², X¹, X² and y are as previously defined.

In some aspects, the compound has general Formula IVb:

wherein R, R¹, R², and y are as previously defined.

In some aspects, the compound has general Formula IVc:

wherein R and R², are as previously defined.

In some aspects, the compound has general Formula IVd:

wherein R, R², and X′ are as previously defined.

In some aspects, the compound has general Formula IVe:

wherein R, R², X¹, and X² are as previously defined.

In some aspects, the compound has general Formula IVf:

wherein R, R², X¹, X², and X³ are as previously defined.

In some embodiments, the compound is selected from a Formula presentedabove and X¹ is N and X² is CH. In other embodiments, the compound isselected from a Formula presented above and X¹ is N and X² is N. Inother embodiments, the compound is selected from a Formula presentedabove and X¹ is CH and X² is CH. In other embodiments, the compound isselected from a Formula presented above and X¹ is CH and X² is N.

In some embodiments, the compound is selected from a Formula presentedabove and X¹ is N, X² is CH, X³ is CH, and X⁴ is CH. In otherembodiments, the compound is selected from a Formula presented above andX¹ is CH, X² is N, X³ is CH, and X⁴ is CH. In other embodiments, thecompound is selected from a Formula presented above and X¹ is CH, X² isN, X³ is N, and X⁴ is CH. In other embodiments, the compound is selectedfrom a Formula presented above and X¹ is CH, X² is N, X³ is CH, and X⁴is N. In other embodiments, the compound is selected from a Formulapresented above and X¹ is N, X² is CH, X³ is N, and X⁴ is CH. In otherembodiments, the compound is selected from a Formula presented above andX¹ is N, X² is CH, X³ is CH, and X⁴ is N.

In some embodiments, the compound is selected from a Formula presentedabove and R² is

wherein P* is a 4- to 8-membered mono- or bicyclic saturatedheterocyclyl group and R^(2*), R^(x1) and t are as previously defined.

In some embodiments, the compound is selected from a Formula presentedabove and R² is

wherein P* is a 4- to 8-membered mono- or bicyclic saturatedheterocyclyl group, R^(x1) is hydrogen or unsubstituted C₁-C₄ alkyl andR²* is as previously defined.

In some embodiments, the compound is selected from a Formula presentedabove and R² is selected from

In some embodiments, the compound is selected from a Formula presentedabove and R² is selected from,

In some embodiments, the compound is selected from a Formula presentedabove and R is alkyl.

In some embodiments, the compound is selected from a Formula presentedabove and R is hydrogen.

In some embodiments R^(x) is further substituted with a substituentchosen from: -(alkylene)_(m)-CN, -(alkylene)_(m)-OR⁵*,-(alkylene)_(m)-S(O)_(n)—R⁵*, -(alkylene)_(m)-NR³*R⁴*,-(alkylene)_(m)-C(O)—R⁵*, -(alkylene)_(m)-C(═S)R⁵*,-(alkylene)_(m)-C(═O)O R⁵*, -(alkylene)_(m)-OC(═O)R⁵*,-(alkylene)_(m)-C(S)—OR⁵*, -(alkylene)_(m)-C(O)—NR³*R⁴*,-(alkylene)_(m)-C(S)—NR³*R⁴*, -(alkylene)_(m)-N(R³*)—C(O)NR³*R⁴*,-(alkylene)_(m)-N(R³*)—C(S)—NR³*R⁴*, -(alkylene)_(m)-N(R³*)—C(O)—R⁵*,-(alkylene)_(m)-N(R³*)—C(S)—R⁵*, -(alkylene)_(m)-O—C(O)—NR³*R⁴*,-(alkylene)_(m)-O—C(S)—NR³*R⁴*, -(alkylene)_(m)-SO₂—NR³*R⁴*,-(alkylene)_(m)-N(R³*)—SO₂—R⁵*, -(alkylene)_(m)-N(R³*)—SO₂—NR³*R⁴*,-(alkylene)_(m)-N(R³*)—C(O)—OR⁵*, -(alkylene)_(m)-N(R³*)—C(S)—OR⁵*, and-(alkylene)_(m)-N(R³*)—SO₂—R⁵*;

R³* and R⁴* at each occurrence are independently selected from:

(i) hydrogen or

(ii) alkyl, alkenyl, alkynyl cycloalkyl, heterocyclo, aryl, heteroaryl,cycloalkylalkyl, heterocycloalkyl, arylalkyl, or heteroarylalkyl any ofwhich may be optionally independently substituted with one or more R^(x)groups as allowed by valance; or R³* and R⁴* together with the nitrogenatom to which they are attached may combine to form a heterocyclo ringoptionally independently substituted with one or more R^(x) groups asallowed by valance.

R⁵* is independently selected at each occurrence from:

(i) hydrogen or

(ii) alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl,cycloalkylalkyl, heterocycloalkyl, arylalkyl, or heteroarylalkyl any ofwhich may be optionally independently substituted with one or more R^(x)groups as allowed by valance;

In some embodiments, the compound of the present invention is selectedfrom:

wherein

R² is selected from,

II. Terminology

Compounds are described using standard nomenclature. Unless definedotherwise, all technical and scientific terms used herein have the samemeaning as is commonly understood by one of skill in the art to whichthis invention belongs.

The compounds in any of the Formulas described herein include racemates,enantiomers, mixtures of enantiomers, diastereomers, mixtures ofdiastereomers, tautomers, N-oxides, isomers; such as rotamers, as ifeach is specifically described.

The terms “a” and “an” do not denote a limitation of quantity, butrather denote the presence of at least one of the referenced item. Theterm “or” means “and/or”. Recitation of ranges of values are merelyintended to serve as a shorthand method of referring individually toeach separate value falling within the range, unless otherwise indicatedherein, and each separate value is incorporated into the specificationas if it were individually recited herein. The endpoints of all rangesare included within the range and independently combinable. All methodsdescribed herein can be performed in a suitable order unless otherwiseindicated herein or otherwise clearly contradicted by context. The useof examples, or exemplary language (e.g., “such as”), is intended merelyto better illustrate the invention and does not pose a limitation on thescope of the invention unless otherwise claimed. Unless definedotherwise, technical and scientific terms used herein have the samemeaning as is commonly understood by one of skill in the art to whichthis invention belongs.

The present invention includes compounds of Formula I, Formula II,Formula III and Formula IV with at least one desired isotopicsubstitution of an atom, at an amount above the natural abundance of theisotope, i.e., enriched. Isotopes are atoms having the same atomicnumber but different mass numbers, i.e., the same number of protons buta different number of neutrons.

Examples of isotopes that can be incorporated into compounds of theinvention include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorous, fluorine, chlorine and iodine such as ²H, ³H, ¹¹C, ¹³C,¹⁴C, ¹⁵N, ¹⁸F ³¹P, ³²P, ³⁵S, ³⁶CI, and ¹²⁵I respectively. In onenon-limiting embodiment, isotopically labelled compounds can be used inmetabolic studies (with ¹⁴C), reaction kinetic studies (with, forexample ²H or ³H), detection or imaging techniques, such as positronemission tomography (PET) or single-photon emission computed tomography(SPECT) including drug or substrate tissue distribution assays, or inradioactive treatment of patients. In particular, an ¹⁸F labeledcompound may be particularly desirable for PET or SPECT studies.Isotopically labeled compounds of this invention and prodrugs thereofcan generally be prepared by carrying out the procedures disclosed inthe schemes or in the examples and preparations described below bysubstituting a readily available isotopically labeled reagent for anon-isotopically labeled reagent.

By way of general example and without limitation, isotopes of hydrogen,for example, deuterium (²H) and tritium (³H) may be used anywhere indescribed structures that achieves the desired result. Alternatively orin addition, isotopes of carbon, e.g., ¹³C and ¹⁴C, may be used.

Isotopic substitutions, for example deuterium substitutions, can bepartial or complete. Partial deuterium substitution means that at leastone hydrogen is substituted with deuterium. In certain embodiments, theisotope is 90, 95 or 99% or more enriched in an isotope at any locationof interest. In one non-limiting embodiment, deuterium is 90, 95 or 99%enriched at a desired location.

In one non-limiting embodiment, the substitution of a hydrogen atom fora deuterium atom can be provided in any of Formula I, Formula II,Formula III, or Formula IV. In one non-limiting embodiment, thesubstitution of a hydrogen atom for a deuterium atom occurs within agroup selected from any of R, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰,R¹¹, R¹², R¹³, R¹⁴, R¹⁵, and R^(x). For example, when any of the groupsare, or contain for example through substitution, methyl, ethyl, ormethoxy, the alkyl residue may be deuterated (in non-limitingembodiments, CDH₂, CD₂H, CD₃, CH₂CD₃, CD₂CD₃, CHDCH₂D, CH₂CD₃, CHDCHD₂,OCDH₂, OCD₂H, or OCD₃ etc.). In certain other embodiments, when twosubstituents are combined to form a cycle the unsubstituted carbons maybe deuterated.

The compound of the present invention may form a solvate with solvents(including water). Therefore, in one non-limiting embodiment, theinvention includes a solvated form of the compound. The term “solvate”refers to a molecular complex of a compound of the present invention(including a salt thereof) with one or more solvent molecules.Non-limiting examples of solvents are water, ethanol, dimethylsulfoxide, acetone and other common organic solvents. The term “hydrate”refers to a molecular complex comprising a compound of the invention andwater. Pharmaceutically acceptable solvates in accordance with theinvention include those wherein the solvent may be isotopicallysubstituted, e.g. D₂O, d₆-acetone, d₆-DMSO. A solvate can be in a liquidor solid form.

A dash (“-”) that is not between two letters or symbols is used toindicate a point of attachment for a substituent. For example, —(C═O)NH₂is attached through carbon of the keto (C═O) group.

“Alkyl” is a branched or straight chain saturated aliphatic hydrocarbongroup. In one non-limiting embodiment, the alkyl group contains from 1to about 12 carbon atoms, more generally from 1 to about 6 carbon atomsor from 1 to about 4 carbon atoms. In one non-limiting embodiment, thealkyl contains from 1 to about 8 carbon atoms. In certain embodiments,the alkyl is C₁-C₂, C₁-C₃, C₁-C₄, C₁-C₅, or C₁-C₆. The specified rangesas used herein indicate an alkyl group having each member of the rangedescribed as an independent species. For example, the term C₁-C₆ alkylas used herein indicates a straight or branched alkyl group having from1, 2, 3, 4, 5, or 6 carbon atoms and is intended to mean that each ofthese is described as an independent species. For example, the termC₁-C₄ alkyl as used herein indicates a straight or branched alkyl grouphaving from 1, 2, 3, or 4 carbon atoms and is intended to mean that eachof these is described as an independent species. Examples of alkylinclude, but are not limited to, methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, tert-pentyl,neopentyl, n-hexyl, 2-methylpentane, 3-methylpentane,2,2-dimethylbutane, and 2,3-dimethylbutane. In an alternativeembodiment, the alkyl group is optionally substituted. The term “Alkyl”also encompasses cycloalkyl or carbocyclic groups. For example, when aterm is used that includes “alk” then “cycloalkyl” or “carbocyclic” canbe considered part of the definition, unless unambiguously excluded bythe context. For example, and without limitation, the terms alkyl,alkoxy, haloalkyl, etc. can all be considered to include the cyclicforms of alkyl, unless unambiguously excluded by context.

“Alkenyl” is a linear or branched aliphatic hydrocarbon groups havingone or more carbon-carbon double bonds that may occur at a stable pointalong the chain. The specified ranges as used herein indicate an alkenylgroup having each member of the range described as an independentspecies, as described above for the alkyl moiety. Examples of alkenylradicals include, but are not limited to ethenyl, propenyl, allyl,propenyl, butenyl and 4-methylbutenyl. The term “alkenyl” also embodies“cis” and “trans” alkenyl geometry, or alternatively, “E” and “Z”alkenyl geometry. In an alternative embodiment, the alkenyl group isoptionally substituted. The term “Alkenyl” also encompasses cycloalkylor carbocyclic groups possessing at least one point of unsaturation.

“Alkynyl” is a branched or straight chain aliphatic hydrocarbon grouphaving one or more carbon-carbon triple bonds that may occur at anystable point along the chain. The specified ranges as used hereinindicate an alkynyl group having each member of the range described asan independent species, as described above for the alkyl moiety.Examples of alkynyl include, but are not limited to, ethynyl, propynyl,1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl,4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl and 5-hexynyl. Inan alternative embodiment, the alkynyl group is optionally substituted.The term “Alkynyl” also encompasses cycloalkyl or carbocyclic groupspossessing at least one point of unsaturation.

“Halo” and “Halogen” is fluorine, chlorine, bromine or iodine.

“Haloalkyl” is a branched or straight-chain alkyl groups substitutedwith 1 or more halo atoms described above, up to the maximum allowablenumber of halogen atoms. Examples of haloalkyl groups include, but arenot limited to, fluoromethyl, difluoromethyl, trifluoromethyl,chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl,heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl,difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl.“Perhaloalkyl” means an alkyl group having all hydrogen atoms replacedwith halogen atoms. Examples include but are not limited to,trifluoromethyl and pentafluoroethyl.

“Haloalkoxy” indicates a haloalkyl group as defined herein attachedthrough an oxygen bridge (oxygen of an alcohol radical).

As used herein, “aryl” refers to a radical of a monocyclic or polycyclic(e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6,10, or 14 π electrons shared in a cyclic array) having 6-14 ring carbonatoms and zero heteroatoms provided in the aromatic ring system (“C₆₋₁₄aryl”). In some embodiments, an aryl group has 6 ring carbon atoms (“C₆aryl”; e.g., phenyl). In some embodiments, an aryl group has 10 ringcarbon atoms (“C₁₀ aryl”; e.g., naphthyl such as 1-naphthyl and2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms(“C₁₄ aryl”; e.g., anthracyl). “Aryl” also includes ring systems whereinthe aryl ring, as defined above, is fused with one or more carbocyclylor heterocyclyl groups wherein the radical or point of attachment is onthe aryl ring, and in such instances, the number of carbon atomscontinue to designate the number of carbon atoms in the aryl ringsystem. The one or more fused carbocyclyl or heterocyclyl groups can be4 to 7 or 5 to 7-membered saturated or partially unsaturated carbocyclylor heterocyclyl groups that optionally contain 1, 2 or 3 heteroatomsindependently selected from nitrogen, oxygen, phosphorus, sulfur,silicon and boron, to form, for example, a 3,4-methylenedioxyphenylgroup. In one non-limiting embodiment, aryl groups are pendant. Anexample of a pendant ring is a phenyl group substituted with a phenylgroup. In an alternative embodiment, the aryl group is optionallysubstituted as described above. In certain embodiments, the aryl groupis an unsubstituted C₆₋₁₄ aryl. In certain embodiments, the aryl groupis a substituted C₆₋₁₄ aryl. An aryl group may be optionally substitutedwith one or more functional groups that include but are not limited to,halo, hydroxy, nitro, amino, cyano, haloalkyl, aryl, heteroaryl, andheterocyclo.

The term “heterocyclyl” (or “heterocyclo”) includes saturated, andpartially saturated heteroatom-containing ring radicals, where theheteroatoms may be selected from nitrogen, sulfur and oxygen.Heterocyclic rings comprise monocyclic 6-8 membered rings, as well as5-16 membered bicyclic ring systems (which can include bridged fused andspiro-fused bicyclic ring systems). It does not include rings containing—O—O—. —O—S— or —S—S— portions. Said “heterocyclyl” group may beoptionally substituted with 1 to 3 substituents that include but are notlimited to, hydroxyl, Boc, halo, haloalkyl, cyano, alkyl, aralkyl, oxo,alkoxy, and amino. Examples of saturated heterocyclo groups includesaturated 3- to 6-membered heteromonocyclic groups containing 1 to 4nitrogen atoms [e.g. pyrrolidinyl, imidazolidinyl, piperidinyl,pyrrolinyl, piperazinyl]; saturated 3 to 6-membered heteromonocyclicgroup containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g.morpholinyl]; saturated 3 to 6-membered heteromonocyclic groupcontaining 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g.,thiazolidinyl]. Examples of partially saturated heterocyclyl radicalsinclude but are not limited to, dihydrothienyl, dihydropyranyl,dihydrofuryl, and dihydrothiazolyl. Examples of partially saturated andsaturated heterocyclo groups include but are not limited to,pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, pyrazolidinyl,piperazinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl,dihydrothienyl, 2,3-dihydro-benzo[1,4]dioxanyl, indolinyl, isoindolinyl,dihydrobenzothienyl, dihydrobenzofuryl, isochromanyl, chromanyl,1,2-dihydroquinolyl, 1,2,3,4-tetrahydro-isoquinolyl,1,2,3,4-tetrahydro-quinolyl, 2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorenyl,5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinolyl,3,4-dihydro-2H-benzo[1,4]oxazinyl, benzo[1,4]dioxanyl,2,3-dihydro-1H-1λ′-benzo[d]isothiazol-6-yl, dihydropyranyl, dihydrofuryland dihydrothiazolyl.

Heterocyclo groups also include radicals where heterocyclic radicals arefused/condensed with aryl radicals: such as unsaturated condensedheterocyclic group containing 1 to 5 nitrogen atoms, for example,indoline, isoindoline, unsaturated condensed heterocyclic groupcontaining 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, unsaturatedcondensed heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3nitrogen atoms, and saturated, partially unsaturated and unsaturatedcondensed heterocyclic group containing 1 to 2 oxygen or sulfur atoms.

The term “heteroaryl” denotes aryl ring systems that contain one or moreheteroatoms selected from O, N and S, wherein the ring nitrogen andsulfur atom(s) are optionally oxidized, and nitrogen atom(s) areoptionally quarternized. Examples include but are not limited to,unsaturated 5 to 6 membered heteromonocyclyl groups containing 1 to 4nitrogen atoms, such as pyrrolyl, imidazolyl, pyrazolyl, 2-pyridyl,3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl[e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl];unsaturated 5- to 6-membered heteromonocyclic groups containing anoxygen atom, for example, pyranyl, 2-furyl, 3-furyl, etc.; unsaturated 5to 6-membered heteromonocyclic groups containing a sulfur atom, forexample, 2-thienyl, 3-thienyl, etc.; unsaturated 5- to 6-memberedheteromonocyclic groups containing 1 to 2 oxygen atoms and 1 to 3nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl [e.g.,1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl]; unsaturated 5to 6-membered heteromonocyclic groups containing 1 to 2 sulfur atoms and1 to 3 nitrogen atoms, for example, thiazolyl, thiadiazolyl [e.g.,1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl].

The term “sulfonyl”, whether used alone or linked to other terms such asalkylsulfonyl, denotes respectively divalent radicals —SO₂—.

The terms “carboxy” or “carboxyl”, whether used alone or with otherterms, such as “carboxyalkyl”, denotes —C(O)—OH.

The term “carbonyl”, whether used alone or with other terms, such as“aminocarbonyl”, denotes —C(O)—.

The term “aminocarbonyl” denotes an amide group of the formula—C(O)—NH₂.

The terms “heterocycloalkyl” denotes heterocyclic-substituted alkylradicals. Examples include but are not limited to, piperidylmethyl andmorpholinylethyl.

“Arylalkyl” is an aryl group as defined herein attached through an alkylgroup. Non-limiting examples of arylalkyl groups include:

“Heteroarylalkyl” is a heteroaryl group as defined herein attachedthrough an alkyl group. Non-limiting examples of heteroarylalkyl groupsinclude:

“Aryloxy” is an aryl group as defined herein attached through a —O—linker. Non-limiting examples of aryloxy groups include:

As used herein, “carbocyclyl”, “carbocyclic”, “carbocycle” or“cycloalkyl” is a saturated or partially unsaturated (i.e., notaromatic) group containing all carbon ring atoms and from 3 to 14 ringcarbon atoms (“C₃₋₁₄ carbocyclyl”) and zero heteroatoms in thenon-aromatic ring system. In some embodiments, a carbocyclyl group has 3to 10 ring carbon atoms (“C₃₋₁₀ carbocyclyl”). In some embodiments, acarbocyclyl group has 3 to 9 ring carbon atoms (“C₃₋₉ carbocyclyl”). Insome embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms(“C₃₋₈ carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to7 ring carbon atoms (“C₃₋₇ carbocyclyl”). In some embodiments, acarbocyclyl group has 3 to 6 ring carbon atoms (“C₃₋₆ carbocyclyl”). Insome embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms(“C₄₋₆ carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to6 ring carbon atoms (“C₅₋₆ carbocyclyl”). In some embodiments, acarbocyclyl group has 5 to 10 ring carbon atoms (“C₅₋₁₀ carbocyclyl”).Exemplary C₃₋₆ carbocyclyl groups include, without limitation,cyclopropyl (C₃), cyclopropenyl (C₃), cyclobutyl (C₄), cyclobutenyl(C₄), cyclopentyl (C₅), cyclopentenyl (C₅), cyclohexyl (C₆),cyclohexenyl (C₆), cyclohexadienyl (C₆), and the like. Exemplary C₃₋₈carbocyclyl groups include, without limitation, the aforementioned C₃₋₆carbocyclyl groups as well as cycloheptyl (C₇), cycloheptenyl (C₇),cycloheptadienyl (C₇), cycloheptatrienyl (C₇), cyclooctyl (C₈),cyclooctenyl (C₈), and the like. Exemplary C₃₋₁₀ carbocyclyl groupsinclude, without limitation, the aforementioned C₃₋₈ carbocyclyl groupsas well as cyclononyl (C₉), cyclononenyl (C₉), cyclodecyl (C₁₀),cyclodecenyl (C₁₀), and the like. As the foregoing examples illustrate,in certain embodiments, the carbocyclyl group can be saturated or cancontain one or more carbon-carbon double or triple bonds. In analternative embodiment, “Carbocyclyl” also includes ring systems whereinthe carbocyclyl ring, as defined above, is fused with one or moreheterocyclyl, aryl or heteroaryl groups wherein the point of attachmentis on the carbocyclyl ring, and in such instances, the number of carbonscontinue to designate the number of carbons in the carbocyclic ringsystem. In an alternative embodiment, each instance of carbocycle isoptionally substituted with one or more substituents. In certainembodiments, the carbocyclyl group is an unsubstituted C₃₋₁₄carbocyclyl. In certain embodiments, the carbocyclyl group is asubstituted C₃₋₁₄ carbocyclyl.

“Cycloalkylalkyl” is an cycloalkyl group as defined herein attachedthrough an alkyl group. Non-limiting examples of cycloalkylalkyl groupsinclude:

The term “oxo” as used herein contemplates an oxygen atom attached witha double bond.

III. Methods of Treatment

In one aspect, a method of treating a proliferative disorder in a host,including a human, is provided comprising administering an effectiveamount of a compound of Formula I, Formula II, Formula III, or FormulaIV.

or its pharmaceutically acceptable salt, N-oxide, deuterated derivative,prodrug, and/or a pharmaceutically acceptable composition thereof asdescribed herein optionally in a pharmaceutically acceptable carrier.Non-limiting examples of disorders include tumors, cancers, disordersrelated to abnormal cellular proliferation, inflammatory disorders,immune disorders, and autoimmune disorders.

A compound of Formula I, Formula II, Formula III, or Formula IV isuseful as therapeutic agents when administered in an effective amount toa host, including a human, to treat a tumor, cancer (solid, non-solid,diffuse, hematological, etc.), abnormal cellular proliferation, immunedisorder, inflammatory disorder, blood disorder, a myelo- orlymphoproliferative disorder such as B- or T-cell lymphomas, multiplemyeloma, breast cancer, prostate cancer, AML, ALL, ACL, lung cancer,pancreatic cancer, colon cancer, skin cancer, melanoma, Waldenstrom'smacroglobulinemia, Wiskott-Aldrich syndrome, or a post-transplantlymphoproliferative disorder; an autoimmune disorder, for example,Lupus, Crohn's Disease, Addison disease, Celiac disease,dermatomyositis, Graves disease, thyroiditis, multiple sclerosis,pernicious anemia, reactive arthritis, or type I diabetes; a disease ofcardiologic malfunction, including hypercholesterolemia; an infectiousdisease, including a viral and/or bacterial infection; an inflammatorycondition, including asthma, chronic peptic ulcers, tuberculosis,rheumatoid arthritis, periodontitis, ulcerative colitis, or hepatitis.

Exemplary proliferative disorders include, but are not limited to,benign growths, neoplasms, tumors, cancer (Rb positive or Rb negative),autoimmune disorders, inflammatory disorders graft-versus-hostrejection, and fibrotic disorders.

Non-limiting examples of cancers that can be treated according to thepresent invention include, but are not limited to, acoustic neuroma,adenocarcinoma, adrenal gland cancer, anal cancer, angiosarcoma (e.g.,lymphangiosarcoma, lymphangioendotheliosarcoma, hemangiosarcoma),appendix cancer, benign monoclonal gammopathy, biliary cancer (e.g.,cholangiocarcinoma), bladder cancer, breast cancer (e.g., adenocarcinomaof the breast, papillary carcinoma of the breast, mammary cancer,medullary carcinoma of the breast), brain cancer (e.g., meningioma;glioma, e.g., astrocytoma, oligodendroglioma; medulloblastoma), bronchuscancer, carcinoid tumor, cervical cancer (e.g., cervicaladenocarcinoma), choriocarcinoma, chordoma, craniopharyngioma,colorectal cancer (e.g., colon cancer, rectal cancer, colorectaladenocarcinoma), epithelial carcinoma, ependymoma, endotheliosarcoma(e.g., Kaposi's sarcoma, multiple idiopathic hemorrhagic sarcoma),endometrial cancer (e.g., uterine cancer, uterine sarcoma), esophagealcancer (e.g., adenocarcinoma of the esophagus, Barrett'sadenocarcinoma), Ewing's sarcoma, eye cancer (e.g., intraocularmelanoma, retinoblastoma), familiar hypereosinophilia, gall bladdercancer, gastric cancer (e.g., stomach adenocarcinoma), gastrointestinalstromal tumor (GIST), head and neck cancer (e.g., head and neck squamouscell carcinoma, oral cancer (e.g., oral squamous cell carcinoma (OSCC),throat cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngealcancer, oropharyngeal cancer)), hematopoietic cancers (e.g., leukemiasuch as acute lymphocytic leukemia (ALL)—also known as acutelymphoblastic leukemia or acute lymphoid leukemia (e.g., B-cell ALL,T-cell ALL), acute myelocytic leukemia (AML) (e.g., B-cell AML, T-cellAML), chronic myelocytic leukemia (CML) (e.g., B-cell CML, T-cell CML),and chronic lymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL);lymphoma such as Hodgkin lymphoma (HL) (e.g., B-cell HL, T-cell HL) andnon-Hodgkin lymphoma (NHL) (e.g., B-cell NHL such as diffuse large celllymphoma (DLCL) (e.g., diffuse large B-cell lymphoma (DLBCL)),follicular lymphoma, chronic lymphocytic leukemia/small lymphocyticlymphoma (CLL/SLL), mantle cell lymphoma (MCL), marginal zone B-celllymphomas (e.g., mucosa-associated lymphoid tissue (MALT) lymphomas,nodal marginal zone B-cell lymphoma, splenic marginal zone B-celllymphoma), primary mediastinal B-cell lymphoma, Burkitt lymphoma,lymphoplasmacytic lymphoma (i.e., “Waldenström's macroglobulinemia”),hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursorB-lymphoblastic lymphoma and primary central nervous system (CNS)lymphoma; and T-cell NHL such as precursor T-lymphoblasticlymphoma/leukemia, peripheral T-cell lymphoma (PTCL) (e.g., cutaneousT-cell lymphoma (CTCL) (e.g., mycosis fungiodes, Sezary syndrome),angioimmunoblastic T-cell lymphoma, extranodal natural killer T-celllymphoma, enteropathy type T-cell lymphoma, subcutaneouspanniculitis-like T-cell lymphoma, anaplastic large cell lymphoma); amixture of one or more leukemia/lymphoma as described above; andmultiple myeloma (MM)), heavy chain disease (e.g., alpha chain disease,gamma chain disease, mu chain disease), hemangioblastoma, inflammatorymyofibroblastic tumors, immunocytic amyloidosis, kidney cancer (e.g.,nephroblastoma a.k.a. Wilms' tumor, renal cell carcinoma), liver cancer(e.g., hepatocellular cancer (HCC), malignant hepatoma), lung cancer(e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-smallcell lung cancer (NSCLC), adenocarcinoma of the lung), leiomyosarcoma(LMS), mastocytosis (e.g., systemic mastocytosis), myelodysplasticsyndrome (MDS), mesothelioma, myeloproliferative disorder (MPD) (e.g.,polycythemia Vera (PV), essential thrombocytosis (ET), agnogenic myeloidmetaplasia (AMM) a.k.a. myelofibrosis (MF), chronic idiopathicmyelofibrosis, chronic myelocytic leukemia (CML), chronic neutrophilicleukemia (CNL), hypereosinophilic syndrome (HES)), neuroblastoma,neurofibroma (e.g., neurofibromatosis (NF) type 1 or type 2,schwannomatosis), neuroendocrine cancer (e.g., gastroenteropancreaticneuroendoctrine tumor (GEP-NET), carcinoid tumor), osteosarcoma, ovariancancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarianadenocarcinoma), papillary adenocarcinoma, pancreatic cancer (e.g.,pancreatic andenocarcinoma, intraductal papillary mucinous neoplasm(IPMN), Islet cell tumors), penile cancer (e.g., Paget's disease of thepenis and scrotum), pinealoma, primitive neuroectodermal tumor (PNT),prostate cancer (e.g., prostate adenocarcinoma), rectal cancer,rhabdomyosarcoma, salivary gland cancer, skin cancer (e.g., squamouscell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cellcarcinoma (BCC)), small bowel cancer (e.g., appendix cancer), softtissue sarcoma (e.g., malignant fibrous histiocytoma (MFH), liposarcoma,malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma,fibrosarcoma, myxosarcoma), sebaceous gland carcinoma, sweat glandcarcinoma, synovioma, testicular cancer (e.g., seminoma, testicularembryonal carcinoma), thyroid cancer (e.g., papillary carcinoma of thethyroid, papillary thyroid carcinoma (PTC), medullary thyroid cancer),urethral cancer, vaginal cancer and vulvar cancer (e.g., Paget's diseaseof the vulva).

In another embodiment, the disorder is myelodysplastic syndrome (MDS).

In certain embodiments, the cancer is a hematopoietic cancer. In certainembodiments, the hematopoietic cancer is a lymphoma. In certainembodiments, the hematopoietic cancer is a leukemia. In certainembodiments, the leukemia is acute myelocytic leukemia (AML).

In certain embodiments, the proliferative disorder is amyeloproliferative neoplasm. In certain embodiments, themyeloproliferative neoplasm (MPN) is primary myelofibrosis (PMF).

In certain embodiments, the cancer is a solid tumor. A solid tumor, asused herein, refers to an abnormal mass of tissue that usually does notcontain cysts or liquid areas. Different types of solid tumors are namedfor the type of cells that form them. Examples of classes of solidtumors include, but are not limited to, sarcomas, carcinomas, andlymphomas, as described above herein. Additional examples of solidtumors include, but are not limited to, squamous cell carcinoma, coloncancer, breast cancer, prostate cancer, lung cancer, liver cancer,pancreatic cancer, and melanoma.

In certain embodiments, the condition treated with a compound Formula I,Formula II, Formula III, or Formula IV is a disorder related to abnormalcellular proliferation.

Abnormal cellular proliferation, notably hyperproliferation, can occuras a result of a wide variety of factors, including genetic mutation,infection, exposure to toxins, autoimmune disorders, and benign ormalignant tumor induction.

There are a number of skin disorders associated with cellularhyperproliferation. Psoriasis, for example, is a benign disease of humanskin generally characterized by plaques covered by thickened scales. Thedisease is caused by increased proliferation of epidermal cells ofunknown cause. Chronic eczema is also associated with significanthyperproliferation of the epidermis. Other diseases caused byhyperproliferation of skin cells include atopic dermatitis, lichenplanus, warts, pemphigus vulgaris, actinic keratosis, basal cellcarcinoma and squamous cell carcinoma.

Other hyperproliferative cell disorders include blood vesselproliferation disorders, fibrotic disorders, autoimmune disorders,graft-versus-host rejection, tumors and cancers.

Blood vessel proliferative disorders include angiogenic and vasculogenicdisorders. Proliferation of smooth muscle cells in the course ofdevelopment of plaques in vascular tissue cause, for example,restenosis, retinopathies and atherosclerosis. Both cell migration andcell proliferation play a role in the formation of atheroscleroticlesions.

Fibrotic disorders are often due to the abnormal formation of anextracellular matrix. Examples of fibrotic disorders include hepaticcirrhosis and mesangial proliferative cell disorders. Hepatic cirrhosisis characterized by the increase in extracellular matrix constituentsresulting in the formation of a hepatic scar. Hepatic cirrhosis cancause diseases such as cirrhosis of the liver. An increasedextracellular matrix resulting in a hepatic scar can also be caused byviral infection such as hepatitis. Lipocytes appear to play a major rolein hepatic cirrhosis.

Mesangial disorders are brought about by abnormal proliferation ofmesangial cells. Mesangial hyperproliferative cell disorders includevarious human renal diseases, such as glomerulonephritis, diabeticnephropathy, malignant nephrosclerosis, thrombotic micro-angiopathysyndromes, transplant rejection, and glomerulopathies.

Another disease with a proliferative component is rheumatoid arthritis.Rheumatoid arthritis is generally considered an autoimmune disease thatis thought to be associated with activity of autoreactive T cells, andto be caused by autoantibodies produced against collagen and IgE.

Other disorders that can include an abnormal cellular proliferativecomponent include Bechet's syndrome, acute respiratory distress syndrome(ARDS), ischemic heart disease, post-dialysis syndrome, leukemia,acquired immune deficiency syndrome, vasculitis, lipid histiocytosis,septic shock and inflammation in general.

In certain embodiments, a compound of the present invention and itspharmaceutically acceptable derivatives or pharmaceutically acceptableformulations containing these compounds are also useful in theprevention and treatment of HBV infections and other related conditionssuch as anti-HBV antibody positive and HBV-positive conditions, chronicliver inflammation caused by HBV, cirrhosis, acute hepatitis, fulminanthepatitis, chronic persistent hepatitis, and fatigue. These compounds orformulations can also be used prophylactically to prevent or retard theprogression of clinical illness in individuals who are anti-HBV antibodyor HBV-antigen positive or who have been exposed to HBV.

In certain embodiments, the condition is associated with an immuneresponse.

Cutaneous contact hypersensitivity and asthma are just two examples ofimmune responses that can be associated with significant morbidity.Others include atopic dermatitis, eczema, Sjogren's Syndrome, includingkeratoconjunctivitis sicca secondary to Sjogren's Syndrome, alopeciaareata, allergic responses due to arthropod bite reactions, Crohn'sdisease, aphthous ulcer, iritis, conjunctivitis, keratoconjunctivitis,ulcerative colitis, cutaneous lupus erythematosus, scleroderma,vaginitis, proctitis, and drug eruptions. These conditions may result inany one or more of the following symptoms or signs: itching, swelling,redness, blisters, crusting, ulceration, pain, scaling, cracking, hairloss, scarring, or oozing of fluid involving the skin, eye, or mucosalmembranes.

In atopic dermatitis, and eczema in general, immunologically mediatedleukocyte infiltration (particularly infiltration of mononuclear cells,lymphocytes, neutrophils, and eosinophils) into the skin importantlycontributes to the pathogenesis of these diseases. Chronic eczema alsois associated with significant hyperproliferation of the epidermis.Immunologically mediated leukocyte infiltration also occurs at sitesother than the skin, such as in the airways in asthma and in the tearproducing gland of the eye in keratoconjunctivitis sicca.

In one non-limiting embodiment compounds of the present invention areused as topical agents in treating contact dermatitis, atopicdermatitis, eczematous dermatitis, psoriasis, Sjogren's Syndrome,including keratoconjunctivitis sicca secondary to Sjogren's Syndrome,alopecia areata, allergic responses due to arthropod bite reactions,Crohn's disease, aphthous ulcer, iritis, conjunctivitis,keratoconjunctivitis, ulcerative colitis, asthma, allergic asthma,cutaneous lupus erythematosus, scleroderma, vaginitis, proctitis, anddrug eruptions. The novel method may also be useful in reducing theinfiltration of skin by malignant leukocytes in diseases such as mycosisfungoides. These compounds can also be used to treat anaqueous-deficient dry eye state (such as immune mediatedkeratoconjunctivitis) in a patient suffering therefrom, by administeringthe compound topically to the eye.

The term “neoplasia” or “cancer” is used throughout the specification torefer to the pathological process that results in the formation andgrowth of a cancerous or malignant neoplasm, i.e., abnormal tissue(solid) or cells (non-solid) that grow by cellular proliferation, oftenmore rapidly than normal and continues to grow after the stimuli thatinitiated the new growth cease. Malignant neoplasms show partial orcomplete lack of structural organization and functional coordinationwith the normal tissue and most invade surrounding tissues, canmetastasize to several sites, are likely to recur after attemptedremoval and may cause the death of the patient unless adequatelytreated. As used herein, the term neoplasia is used to describe allcancerous disease states and embraces or encompasses the pathologicalprocess associated with malignant hematogenous, ascitic and solidtumors. Exemplary cancers which may be treated by the present disclosedcompounds either alone or in combination with at least one additionalanti-cancer agent include squamous-cell carcinoma, basal cell carcinoma,adenocarcinoma, hepatocellular carcinomas, and renal cell carcinomas,cancer of the bladder, bowel, breast, cervix, colon, esophagus, head,kidney, liver, lung, neck, ovary, pancreas, prostate, and stomach;leukemias; benign and malignant lymphomas, particularly Burkitt'slymphoma and Non-Hodgkin's lymphoma benign and malignant melanomas;myeloproliferative diseases; sarcomas, including Ewing's sarcoma,hemangiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcomas, peripheralneuroepithelioma, synovial sarcoma, gliomas, astrocytomas,oligodendrogliomas, ependymomas, gliobastomas, neuroblastomas,ganglioneuromas, gangliogliomas, medulloblastomas, pineal cell tumors,meningiomas, meningeal sarcomas, neurofibromas, and Schwannomas; bowelcancer, breast cancer, prostate cancer, cervical cancer, uterine cancer,lung cancer, ovarian cancer, testicular cancer, thyroid cancer,astrocytoma, esophageal cancer, pancreatic cancer, stomach cancer, livercancer, colon cancer, melanoma; carcinosarcoma, Hodgkin's disease,Wilms' tumor and teratocarcinomas. Additional cancers which may betreated using the disclosed compounds according to the present inventioninclude, for example, acute granulocytic leukemia, acute lymphocyticleukemia (ALL), acute myelogenous leukemia (AML), adenocarcinoma,adenosarcoma, adrenal cancer, adrenocortical carcinoma, anal cancer,anaplastic astrocytoma, angiosarcoma, appendix cancer, astrocytoma,Basal cell carcinoma, B-Cell lymphoma, bile duct cancer, bladder cancer,bone cancer, bone marrow cancer, bowel cancer, brain cancer, brain stemglioma, breast cancer, triple (estrogen, progesterone and HER-2)negative breast cancer, double negative breast cancer (two of estrogen,progesterone and HER-2 are negative), single negative (one of estrogen,progesterone and HER-2 is negative), estrogen-receptor positive,HER2-negative breast cancer, estrogen receptor-negative breast cancer,estrogen receptor positive breast cancer, metastatic breast cancer,luminal A breast cancer, luminal B breast cancer, Her2-negative breastcancer, HER2-positive or negative breast cancer, progesteronereceptor-negative breast cancer, progesterone receptor-positive breastcancer, recurrent breast cancer, carcinoid tumors, cervical cancer,cholangiocarcinoma, chondrosarcoma, chronic lymphocytic leukemia (CLL),chronic myelogenous leukemia (CML), colon cancer, colorectal cancer,craniopharyngioma, cutaneous lymphoma, cutaneous melanoma, diffuseastrocytoma, ductal carcinoma in situ (DCIS), endometrial cancer,ependymoma, epitheloid sarcoma, esophageal cancer, ewing sarcoma,extrahepatic bile duct cancer, eye cancer, fallopian tube cancer,fibrosarcoma, gallbladder cancer, gastric cancer, gastrointestinalcancer, gastrointestinal carcinoid cancer, gastrointestinal stromaltumors (GIST), germ cell tumor glioblastoma multiforme (GBM), glioma,hairy cell leukemia, head and neck cancer, hemangioendothelioma, Hodgkinlymphoma, hypopharyngeal cancer, infiltrating ductal carcinoma (IDC),infiltrating lobular carcinoma (ILC), inflammatory breast cancer (IBC),intestinal Cancer, intrahepatic bile duct cancer, invasive/infiltratingbreast cancer, Islet cell cancer, jaw cancer, Kaposi sarcoma, kidneycancer, laryngeal cancer, leiomyosarcoma, leptomeningeal metastases,leukemia, lip cancer, liposarcoma, liver cancer, lobular carcinoma insitu, low-grade astrocytoma, lung cancer, lymph node cancer, lymphoma,male breast cancer, medullary carcinoma, medulloblastoma, melanoma,meningioma, Merkel cell carcinoma, mesenchymal chondrosarcoma,mesenchymous, mesothelioma metastatic breast cancer, metastatic melanomametastatic squamous neck cancer, mixed gliomas, monodermal teratoma,mouth cancer mucinous carcinoma, mucosal melanoma, multiple myeloma,Mycosis Fungoides, myelodysplastic syndrome, nasal cavity cancer,nasopharyngeal cancer, neck cancer, neuroblastoma, neuroendocrine tumors(NETs), non-Hodgkin's lymphoma, non-small cell lung cancer (NSCLC), oatcell cancer, ocular cancer, ocular melanoma, oligodendroglioma, oralcancer, oral cavity cancer, oropharyngeal cancer, osteogenic sarcoma,osteosarcoma, ovarian cancer, ovarian epithelial cancer ovarian germcell tumor, ovarian primary peritoneal carcinoma, ovarian sex cordstromal tumor, Paget's disease, pancreatic cancer, papillary carcinoma,paranasal sinus cancer, parathyroid cancer, pelvic cancer, penilecancer, peripheral nerve cancer, peritoneal cancer, pharyngeal cancer,pheochromocytoma, pilocytic astrocytoma, pineal region tumor,pineoblastoma, pituitary gland cancer, primary central nervous system(CNS) lymphoma, prostate cancer, rectal cancer, renal cell carcinoma,renal pelvis cancer, rhabdomyosarcoma, salivary gland cancer, softtissue sarcoma, bone sarcoma, sarcoma, sinus cancer, skin cancer, smallcell lung cancer (SCLC), small intestine cancer, spinal cancer, spinalcolumn cancer, spinal cord cancer, squamous cell carcinoma, stomachcancer, synovial sarcoma, T-cell lymphoma, testicular cancer, throatcancer, thymoma/thymic carcinoma, thyroid cancer, tongue cancer, tonsilcancer, transitional cell cancer, tubal cancer, tubular carcinoma,undiagnosed cancer, ureteral cancer, urethral cancer, uterineadenocarcinoma, uterine cancer, uterine sarcoma, vaginal cancer, vulvarcancer, T-cell lineage acute lymphoblastic leukemia (T-ALL), T-celllineage lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, AdultT-cell leukemia, Pre-B ALL, Pre-B lymphomas, large B-cell lymphoma,Burkitts lymphoma, B-cell ALL, Philadelphia chromosome positive ALL,Philadelphia chromosome positive CML, juvenile myelomonocytic leukemia(JMML), acute promyelocytic leukemia (a subtype of AML), large granularlymphocytic leukemia, Adult T-cell chronic leukemia, diffuse large Bcell lymphoma, follicular lymphoma; Mucosa-Associated Lymphatic Tissuelymphoma (MALT), small cell lymphocytic lymphoma, mediastinal large Bcell lymphoma, nodal marginal zone B cell lymphoma (NMZL); splenicmarginal zone lymphoma (SMZL); intravascular large B-cell lymphoma;primary effusion lymphoma; or lymphomatoid granulomatosis; B-cellprolymphocytic leukemia; splenic lymphoma/leukemia, unclassifiable,splenic diffuse red pulp small B-cell lymphoma; lymphoplasmacyticlymphoma; heavy chain diseases, for example, Alpha heavy chain disease,Gamma heavy chain disease, Mu heavy chain disease, plasma cell myeloma,solitary plasmacytoma of bone; extraosseous plasmacytoma; primarycutaneous follicle center lymphoma, T cell/histocyte rich large B-celllymphoma, DLBCL associated with chronic inflammation; Epstein-Barr virus(EBV)+DLBCL of the elderly; primary mediastinal (thymic) large B-celllymphoma, primary cutaneous DLBCL, leg type, ALK+ large B-cell lymphoma,plasmablastic lymphoma; large B-cell lymphoma arising in HHV8-associatedmulticentric, Castleman disease; B-cell lymphoma, unclassifiable, withfeatures intermediate between diffuse large B-cell lymphoma, or B-celllymphoma, unclassifiable, with features intermediate between diffuselarge B-cell lymphoma and classical Hodgkin lymphoma.

In another aspect, a method of increasing BIM expression (e.g., BCLC2L11expression) is provided to induce apoptosis in a cell comprisingcontacting a compound of the present invention or a pharmaceuticallyacceptable composition, salt, isotopic analog, or prodrug thereof withthe cell. In certain embodiments, the method is an in vitro method. Incertain embodiments, the method is an in vivo method. BCL2L11 expressionis tightly regulated in a cell. BCL2L11 encodes for BIM, a proapoptoticprotein. BCL2L11 is downregulated in many cancers and BIM is inhibitedin many cancers, including chronic myelocytic leukemia (CML) andnon-small cell lung cancer (NSCLC) and that suppression of BCL2L11expression can confer resistance to tyrosine kinase inhibitors. See,e.g., Ng et al., Nat. Med. (2012) 18:521-528.

In yet another aspect, a method of treating a condition associated withangiogenesis is provided, such as, for example, a diabetic condition(e.g., diabetic retinopathy), an inflammatory condition (e.g.,rheumatoid arthritis), macular degeneration, obesity, atherosclerosis,or a proliferative disorder, comprising administering to a subject inneed thereof a compound of the present invention or a pharmaceuticallyacceptable composition, salt, isotopic analog, or prodrug thereof.

In certain embodiments, the condition associated with angiogenesis ismacular degeneration. In certain embodiments, provided is a method oftreating macular degeneration comprising administering to a subject inneed thereof a compound of the present invention or a pharmaceuticallyacceptable composition, salt, isotopic analog, or prodrug thereof.

In certain embodiments, the condition associated with angiogenesis isobesity. As used herein, “obesity” and “obese” as used herein, refers toclass I obesity, class II obesity, class III obesity and pre-obesity(e.g., being “over-weight”) as defined by the World Health Organization.In certain embodiments, a method of treating obesity is providedcomprising administering to a subject in need thereof a compound of thepresent invention or a pharmaceutically acceptable composition, salt,isotopic analog, or prodrug thereof.

In certain embodiments, the condition associated with angiogenesis isatherosclerosis. In certain embodiments, provided is a method oftreating atherosclerosis comprising administering to a subject in needthereof a compound of the present invention or a pharmaceuticallyacceptable composition, salt, isotopic analog, or prodrug thereof.

In certain embodiments, the condition associated with angiogenesis is aproliferative disorder. In certain embodiments, provided is a method oftreating a proliferative disorder comprising administering to a subjectin need thereof a compound of the present invention or apharmaceutically acceptable composition, salt, isotopic analog, orprodrug thereof.

IV. Methods to Reduce the Side Effects Related to Chemotherapy

In certain embodiments, compounds of the present invention decrease theeffect of chemotherapeutic agent toxicity on CDK4/6 replicationdependent healthy cells, such as hematopoietic stem cells andhematopoietic progenitor cells (together referred to as HSPCs), and/orrenal epithelial cells, in subjects, typically humans, that will be, arebeing, or have been exposed to the chemotherapeutic agent (typically aDNA-damaging agent).

In one embodiment, the subject has been exposed to a chemotherapeuticagent, and, using a compound described herein, the subject'sCDK4/6-replication dependent healthy cells are placed in G1 arrestfollowing exposure in order to mitigate, for example, DNA damage. In oneembodiment, the compound is administered at least ½ hour, at least 1hour, at least 2 hours, at least 3 hours, at least 4 hours, at least 5hours, at least 6 hours, at least 7 hours, at least 8 hours, at least 10hours, at least 12 hours, at least 14 hours, at least 16 hours, at least18 hours, at least 20 hours or more post chemotherapeutic agentexposure.

In one embodiment, the compound can allow for dose intensification(e.g., more therapy can be given in a fixed period of time) in medicallyrelated chemotherapies, which will translate to better efficacy.Therefore, the presently disclosed methods can result in chemotherapyregimens that are less toxic and more effective.

In some embodiments, the use of a compound described herein may resultin reduced or substantially free of off-target effects, for example,related to inhibition of kinases other than CDK4 and/or CDK6 such asCDK2. Furthermore, in certain embodiments, the use of the compoundsdescribed herein should not induce cell cycle arrest in CDK4/6replication independent cells.

In some embodiments, the use of a compound described herein reduces therisk of undesirable off-target effects including, but not limited to,long term toxicity, anti-oxidant effects, and estrogenic effects.Anti-oxidant effects can be determined by standard assays known in theart. For example, a compound with no significant anti-oxidant effects isa compound that does not significantly scavenge free-radicals, such asoxygen radicals. The anti-oxidant effects of a compound can be comparedto a compound with known anti-oxidant activity, such as genistein. Thus,a compound with no significant anti-oxidant activity can be one that hasless than about 2, 3, 5, 10, 30, or 100 fold anti-oxidant activityrelative to genistein. Estrogenic activities can also be determined viaknown assays. For instance, a non-estrogenic compound is one that doesnot significantly bind and activate the estrogen receptor. A compoundthat is substantially free of estrogenic effects can be one that hasless than about 2, 3, 5, 10, 20, or 100 fold estrogenic activityrelative to a compound with estrogenic activity, e.g., genistein.

V. Methods to Treat Abnormal Proliferation of T-Cells, B-Cells and/orNK-Cells

In certain aspects, the invention includes the use of an effectiveamount of a compound described herein, or its pharmaceuticallyacceptable salt, prodrug or isotopic variant optionally in apharmaceutical composition, to treat a host, typically a human, with aselected cancer, tumor, hyperproliferative condition or an inflammatoryor immune disorder. Some of the disclosed compounds are highly activeagainst T-cell proliferation. Given the paucity of drugs for T-cellcancers and abnormal proliferation, the identification of such usesrepresents a substantial improvement in the medical therapy for thesediseases.

Abnormal proliferation of T-cells, B-cells, and/or NK-cells can resultin a wide range of diseases such as cancer, proliferative disorders andinflammatory/immune diseases. A host, for example a human, afflictedwith any of these disorders can be treated with an effective amount of acompound as described herein to achieve a decrease in symptoms (apalliative agent) or a decrease in the underlying disease (a diseasemodifying agent).

Examples include T-cell or NK-cell lymphoma, for example, but notlimited to: peripheral T-cell lymphoma; anaplastic large cell lymphoma,for example anaplastic lymphoma kinase (ALK) positive, ALK negativeanaplastic large cell lymphoma, or primary cutaneous anaplastic largecell lymphoma; angioimmunoblastic lymphoma; cutaneous T-cell lymphoma,for example mycosis fungoides, Sézary syndrome, primary cutaneousanaplastic large cell lymphoma, primary cutaneous CD30+ T-celllymphoproliferative disorder; primary cutaneous aggressiveepidermotropic CD8+ cytotoxic T-cell lymphoma; primary cutaneousgamma-delta T-cell lymphoma; primary cutaneous small/medium CD4+ T-celllymphoma, and lymphomatoid papulosis; Adult T-cell Leukemia/Lymphoma(ATLL); Blastic NK-cell Lymphoma; Enteropathy-type T-cell lymphoma;Hematosplenic gamma-delta T-cell Lymphoma; Lymphoblastic Lymphoma; NasalNK/T-cell Lymphomas; Treatment-related T-cell lymphomas; for examplelymphomas that appear after solid organ or bone marrow transplantation;T-cell prolymphocytic leukemia; T-cell large granular lymphocyticleukemia; Chronic lymphoproliferative disorder of NK-cells; AggressiveNK cell leukemia; Systemic EBV+ T-cell lymphoproliferative disease ofchildhood (associated with chronic active EBV infection); Hydroavacciniforme-like lymphoma; Adult T-cell leukemia/lymphoma;Enteropathy-associated T-cell lymphoma; Hepatosplenic T-cell lymphoma;or Subcutaneous panniculitis-like T-cell lymphoma.

In one embodiment, a compound disclosed herein, or its salt, prodrug, orisotopic variant can be used in an effective amount to treat a host, forexample a human, with a lymphoma or lymphocytic or myelocyticproliferation disorder or abnormality. For example, the compounds asdescribed herein can be administered to a host suffering from a HodgkinLymphoma or a Non-Hodgkin Lymphoma. For example, the host can besuffering from a Non-Hodgkin Lymphoma such as, but not limited to: anAIDS-Related Lymphoma; Anaplastic Large-Cell Lymphoma;Angioimmunoblastic Lymphoma; Blastic NK-Cell Lymphoma; Burkitt'sLymphoma; Burkitt-like Lymphoma (Small Non-Cleaved Cell Lymphoma);Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma; CutaneousT-Cell Lymphoma; Diffuse Large B-Cell Lymphoma; Enteropathy-Type T-CellLymphoma; Follicular Lymphoma; Hepatosplenic Gamma-Delta T-CellLymphoma; Lymphoblastic Lymphoma; Mantle Cell Lymphoma; Marginal ZoneLymphoma; Nasal T-Cell Lymphoma; Pediatric Lymphoma; Peripheral T-CellLymphomas; Primary Central Nervous System Lymphoma; T-Cell Leukemias;Transformed Lymphomas; Treatment-Related T-Cell Lymphomas; orWaldenstrom's Macroglobulinemia.

Alternatively, a compound disclosed herein, or its salt, prodrug, orisotopic variant can be used in an effective amount to treat a host, forexample a human, with a Hodgkin Lymphoma, such as, but not limited to:Nodular Sclerosis Classical Hodgkin's Lymphoma (CHL); Mixed CellularityCHL; Lymphocyte-depletion CHL; Lymphocyte-rich CHL; LymphocytePredominant Hodgkin Lymphoma; or Nodular Lymphocyte Predominant HL.

Alternatively, a compound disclosed herein, or its salt, prodrug, orisotopic variant can be used in an effective amount to treat a host, forexample a human with a specific B-cell lymphoma or proliferativedisorder such as, but not limited to: multiple myeloma; Diffuse large Bcell lymphoma; Follicular lymphoma; Mucosa-Associated Lymphatic Tissuelymphoma (MALT); Small cell lymphocytic lymphoma; Mediastinal large Bcell lymphoma; Nodal marginal zone B cell lymphoma (NMZL); Splenicmarginal zone lymphoma (SMZL); Intravascular large B-cell lymphoma;Primary effusion lymphoma; or Lymphomatoid granulomatosis; B-cellprolymphocytic leukemia; Hairy cell leukemia; Splenic lymphoma/leukemia,unclassifiable; Splenic diffuse red pulp small B-cell lymphoma; Hairycell leukemia-variant; Lymphoplasmacytic lymphoma; Heavy chain diseases,for example, Alpha heavy chain disease, Gamma heavy chain disease, Muheavy chain disease; Plasma cell myeloma; Solitary plasmacytoma of bone;Extraosseous plasmacytoma; Primary cutaneous follicle center lymphoma; Tcell/histiocyte rich large B-cell lymphoma; DLBCL associated withchronic inflammation; Epstein-Barr virus (EBV)+ DLBCL of the elderly;Primary mediastinal (thymic) large B-cell lymphoma; Primary cutaneousDLBCL, leg type; ALK+ large B-cell lymphoma; Plasmablastic lymphoma;Large B-cell lymphoma arising in HHV8-associated multicentric; Castlemandisease; B-cell lymphoma, unclassifiable, with features intermediatebetween diffuse large B-cell lymphoma; or B-cell lymphoma,unclassifiable, with features intermediate between diffuse large B-celllymphoma and classical Hodgkin lymphoma.

In one embodiment, a compound disclosed herein, or its salt, prodrug, orisotopic variant can be used in an effective amount to treat a host, forexample a human with leukemia. For example, the host may be sufferingfrom an acute or chronic leukemia of a lymphocytic or myelogenousorigin, such as, but not limited to: Acute lymphoblastic leukemia (ALL);Acute myelogenous leukemia (AML); Chronic lymphocytic leukemia (CLL);Chronic myelogenous leukemia (CML); juvenile myelomonocytic leukemia(JMML); hairy cell leukemia (HCL); acute promyelocytic leukemia (asubtype of AML); large granular lymphocytic leukemia; or Adult T-cellchronic leukemia. In one embodiment, the patient suffers from an acutemyelogenous leukemia, for example an undifferentiated AML (M0);myeloblastic leukemia (M1; with/without minimal cell maturation);myeloblastic leukemia (M2; with cell maturation); promyelocytic leukemia(M3 or M3 variant [M3V]); myelomonocytic leukemia (M4 or M4 variant witheosinophilia [M4E]); monocytic leukemia (M5); erythroleukemia (M6); ormegakaryoblastic leukemia (M7).

VI. Pharmaceutical Compositions and Dosage Forms

An active compound described herein, or its salt, isotopic analog, orprodrug can be administered in an effective amount to a host to treatany of the disorders described herein using any suitable approach whichachieves the desired therapeutic result. The amount and timing of activecompound administered will, of course, be dependent on the host beingtreated, the instructions of the supervising medical specialist, on thetime course of the exposure, on the manner of administration, on thepharmacokinetic properties of the particular active compound, and on thejudgment of the prescribing physician. Thus, because of host to hostvariability, the dosages given below are a guideline and the physiciancan titrate doses of the compound to achieve the treatment that thephysician considers appropriate for the host. In considering the degreeof treatment desired, the physician can balance a variety of factorssuch as age and weight of the host, presence of preexisting disease, aswell as presence of other diseases.

The pharmaceutical composition may be formulated as any pharmaceuticallyuseful form, e.g., as an aerosol, a cream, a gel, a pill, an injectionor infusion solution, a capsule, a tablet, a syrup, a transdermal patch,a subcutaneous patch, a dry powder, an inhalation formulation, in amedical device, suppository, buccal, or sublingual formulation,parenteral formulation, or an ophthalmic solution. Some dosage forms,such as tablets and capsules, are subdivided into suitably sized unitdoses containing appropriate quantities of the active components, e.g.,an effective amount to achieve the desired purpose.

The therapeutically effective dosage of any active compound describedherein will be determined by the health care practitioner depending onthe condition, size and age of the patient as well as the route ofdelivery. In one non-limited embodiment, a dosage from about 0.1 toabout 200 mg/kg has therapeutic efficacy, with all weights beingcalculated based upon the weight of the active compound, including thecases where a salt is employed. In one embodiment, the dosage is atabout or greater than 0.1, 0.5, 1, 5, 10, 25, 50, 75, 100, 125, 150,175, or 200 mg/kg. In some embodiments, the dosage may be the amount ofcompound needed to provide a serum concentration of the active compoundof up to about 10 nM, 50 nM, 100 nM, 200 nM, 300 nM, 400 nM, 500 nM, 600nM, 700 nM, 800 nM, 900 nM, 1 μM, 5 μM, 10 μM, 20 μM, 30 μM, or 40 μM.

In certain embodiments, the pharmaceutical composition is in a dosageform that contains from about 0.1 mg to about 2000 mg, from about 10 mgto about 1000 mg, from about 100 mg to about 800 mg, or from about 200mg to about 600 mg of the active compound and optionally from about 0.1mg to about 2000 mg, from about 10 mg to about 1000 mg, from about 100mg to about 800 mg, or from about 200 mg to about 600 mg of anadditional active agent in a unit dosage form. Examples of dosage formswith at least 5, 10, 15, 20, 25, 50, 100, 200, 250, 300, 400, 500, 600,700, or 750 mg of active compound, or its salt. The pharmaceuticalcomposition may also include a molar ratio of the active compound and anadditional active agent, in a ratio that achieves the desired results.

Compounds disclosed herein or used as described herein may beadministered orally, topically, parenterally, by inhalation or spray,sublingually, via implant, including ocular implant, transdermally, viabuccal administration, rectally, as an ophthalmic solution, injection,including ocular injection, intravenous, intramuscular, inhalation,intra-aortal, intracranial, subdermal, intraperitoneal, subcutaneous,transnasal, sublingual, or rectal or by other means, in dosage unitformulations containing conventional pharmaceutically acceptablecarriers. For ocular delivery, the compound can be administered, asdesired, for example, via intravitreal, intrastromal, intracameral,sub-tenon, sub-retinal, retro-bulbar, peribulbar, suprachorodial,conjunctival, subconjunctival, episcleral, periocular, transscleral,retrobulbar, posterior juxtascleral, circumcorneal, or tear ductinjections, or through a mucus, mucin, or a mucosal barrier, in animmediate or controlled release fashion or via an ocular device.

In accordance with the presently disclosed methods, an oraladministration can be in any desired form such as a solid, gel orliquid, including a solution, suspension, or emulsion. In someembodiments, the compounds or salts are administered by inhalation,intravenously, or intramuscularly as a liposomal suspension. Whenadministered through inhalation the active compound or salt may be inthe form of a plurality of solid particles or droplets having anydesired particle size, and for example, from about 0.01, 0.1 or 0.5 toabout 5, 10, 20 or more microns, and optionally from about 1 to about 2microns. Compounds as disclosed in the present invention havedemonstrated good pharmacokinetic and pharmacodynamics properties, forinstance when administered by the oral or intravenous routes.

The pharmaceutical formulations can comprise an active compounddescribed herein or a pharmaceutically acceptable salt thereof, in anypharmaceutically acceptable carrier. If a solution is desired, water maysometimes be the carrier of choice for water-soluble compounds or salts.With respect to the water-soluble compounds or salts, an organicvehicle, such as glycerol, propylene glycol, polyethylene glycol, ormixtures thereof, can be suitable. In the latter instance, the organicvehicle can contain a substantial amount of water. The solution ineither instance can then be sterilized in a suitable manner known tothose in the art, and for illustration by filtration through a0.22-micron filter. Subsequent to sterilization, the solution can bedispensed into appropriate receptacles, such as depyrogenated glassvials. The dispensing is optionally done by an aseptic method.Sterilized closures can then be placed on the vials and, if desired, thevial contents can be lyophilized.

Carriers include excipients and diluents and must be of sufficientlyhigh purity and sufficiently low toxicity to render them suitable foradministration to the patient being treated. The carrier can be inert orit can possess pharmaceutical benefits of its own. The amount of carrieremployed in conjunction with the compound is sufficient to provide apractical quantity of material for administration per unit dose of thecompound.

Classes of carriers include, but are not limited to binders, bufferingagents, coloring agents, diluents, disintegrants, emulsifiers,flavorants, glidents, lubricants, preservatives, stabilizers,surfactants, tableting agents, and wetting agents. Some carriers may belisted in more than one class, for example vegetable oil may be used asa lubricant in some formulations and a diluent in others. Exemplarypharmaceutically acceptable carriers include sugars, starches,celluloses, powdered tragacanth, malt, gelatin; talc, and vegetableoils. Optional active agents may be included in a pharmaceuticalcomposition, which do not substantially interfere with the activity ofthe compound of the present invention.

Additionally, auxiliary substances, such as wetting or emulsifyingagents, biological buffering substances, surfactants, and the like, canbe present in such vehicles. A biological buffer can be any solutionwhich is pharmacologically acceptable and which provides the formulationwith the desired pH, i.e., a pH in the physiologically acceptable range.Examples of buffer solutions include saline, phosphate buffered saline,Tris buffered saline, Hank's buffered saline, and the like.

Depending on the intended mode of administration, the pharmaceuticalcompositions can be in the form of solid, semi-solid or liquid dosageforms, such as, for example, tablets, suppositories, pills, capsules,powders, liquids, suspensions, creams, ointments, lotions or the like,preferably in unit dosage form suitable for single administration of aprecise dosage. The compositions will include an effective amount of theselected drug in combination with a pharmaceutically acceptable carrierand, in addition, can include other pharmaceutical agents, adjuvants,diluents, buffers, and the like.

Thus, the compositions of the disclosure can be administered aspharmaceutical formulations including those suitable for oral (includingbuccal and sub-lingual), rectal, nasal, topical, pulmonary, vaginal orparenteral (including intramuscular, intra-arterial, intrathecal,subcutaneous and intravenous) administration or in a form suitable foradministration by inhalation or insufflation. The preferred manner ofadministration is intravenous or oral using a convenient daily dosageregimen which can be adjusted according to the degree of affliction.

For solid compositions, conventional nontoxic solid carriers include,for example, pharmaceutical grades of mannitol, lactose, starch,magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose,magnesium carbonate, and the like. Liquid pharmaceutically administrablecompositions can, for example, be prepared by dissolving, dispersing,and the like, an active compound as described herein and optionalpharmaceutical adjuvants in an excipient, such as, for example, water,saline, aqueous dextrose, glycerol, ethanol, and the like, to therebyform a solution or suspension. If desired, the pharmaceuticalcomposition to be administered can also contain minor amounts ofnontoxic auxiliary substances such as wetting or emulsifying agents, pHbuffering agents and the like, for example, sodium acetate, sorbitanmonolaurate, triethanolamine sodium acetate, triethanolamine oleate, andthe like. Actual methods of preparing such dosage forms are known, orwill be apparent, to those skilled in this art; for example, seeRemington's Pharmaceutical Sciences, referenced above.

In yet another embodiment is the use of permeation enhancer excipientsincluding polymers such as: polycations (chitosan and its quaternaryammonium derivatives, poly-L-arginine, aminated gelatin); polyanions(N-carboxymethyl chitosan, poly-acrylic acid); and, thiolated polymers(carboxymethyl cellulose-cysteine, polycarbophil-cysteine,chitosan-thiobutylamidine, chitosan-thioglycolic acid,chitosan-glutathione conjugates).

For oral administration, the composition will generally take the form ofa tablet, capsule, a softgel capsule or can be an aqueous or nonaqueoussolution, suspension or syrup. Tablets and capsules are preferred oraladministration forms. Tablets and capsules for oral use can include oneor more commonly used carriers such as lactose and corn starch.Lubricating agents, such as magnesium stearate, are also typicallyadded. Typically, the compositions of the disclosure can be combinedwith an oral, non-toxic, pharmaceutically acceptable, inert carrier suchas lactose, starch, sucrose, glucose, methyl cellulose, magnesiumstearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol andthe like. Moreover, when desired or necessary, suitable binders,lubricants, disintegrating agents, and coloring agents can also beincorporated into the mixture. Suitable binders include starch, gelatin,natural sugars such as glucose or beta-lactose, corn sweeteners, naturaland synthetic gums such as acacia, tragacanth, or sodium alginate,carboxymethylcellulose, polyethylene glycol, waxes, and the like.Lubricants used in these dosage forms include sodium oleate, sodiumstearate, magnesium stearate, sodium benzoate, sodium acetate, sodiumchloride, and the like. Disintegrators include, without limitation,starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.

When liquid suspensions are used, the active agent can be combined withany oral, non-toxic, pharmaceutically acceptable inert carrier such asethanol, glycerol, water, and the like and with emulsifying andsuspending agents. If desired, flavoring, coloring and/or sweeteningagents can be added as well. Other optional components for incorporationinto an oral formulation herein include, but are not limited to,preservatives, suspending agents, thickening agents, and the like.

Parenteral formulations can be prepared in conventional forms, either asliquid solutions or suspensions, solid forms suitable for solubilizationor suspension in liquid prior to injection, or as emulsions. Preferably,sterile injectable suspensions are formulated according to techniquesknown in the art using suitable carriers, dispersing or wetting agentsand suspending agents. The sterile injectable formulation can also be asterile injectable solution or a suspension in a nontoxic parenterallyacceptable diluent or solvent. Among the acceptable vehicles andsolvents that can be employed are water, Ringer's solution and isotonicsodium chloride solution. In addition, sterile, fixed oils, fatty estersor polyols are conventionally employed as solvents or suspending media.In addition, parenteral administration can involve the use of a slowrelease or sustained release system such that a constant level of dosageis maintained.

Parenteral administration includes intraarticular, intravenous,intramuscular, intradermal, intraperitoneal, and subcutaneous routes,and include aqueous and non-aqueous, isotonic sterile injectionsolutions, which can contain antioxidants, buffers, bacteriostats, andsolutes that render the formulation isotonic with the blood of theintended recipient, and aqueous and non-aqueous sterile suspensions thatcan include suspending agents, solubilizers, thickening agents,stabilizers, and preservatives. Administration via certain parenteralroutes can involve introducing the formulations of the disclosure intothe body of a patient through a needle or a catheter, propelled by asterile syringe or some other mechanical device such as an continuousinfusion system. A formulation provided by the disclosure can beadministered using a syringe, injector, pump, or any other devicerecognized in the art for parenteral administration.

In addition to the active compounds or their salts, the pharmaceuticalformulations can contain other additives, such as pH-adjustingadditives. In particular, useful pH-adjusting agents include acids, suchas hydrochloric acid, bases or buffers, such as sodium lactate, sodiumacetate, sodium phosphate, sodium citrate, sodium borate, or sodiumgluconate. Further, the formulations can contain antimicrobialpreservatives. Useful antimicrobial preservatives include methylparaben,propylparaben, and benzyl alcohol. An antimicrobial preservative istypically employed when the formulations is placed in a vial designedfor multi-dose use. The pharmaceutical formulations described herein canbe lyophilized using techniques well known in the art.

For oral administration, a pharmaceutical composition can take the formof a solution suspension, tablet, pill, capsule, powder, and the like.Tablets containing various excipients such as sodium citrate, calciumcarbonate and calcium phosphate may be employed along with variousdisintegrants such as starch (e.g., potato or tapioca starch) andcertain complex silicates, together with binding agents such aspolyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally,lubricating agents such as magnesium stearate, sodium lauryl sulfate,and talc are often very useful for tableting purposes. Solidcompositions of a similar type may be employed as fillers in soft andhard-filled gelatin capsules. Materials in this connection also includelactose or milk sugar as well as high molecular weight polyethyleneglycols. When aqueous suspensions and/or elixirs are desired for oraladministration, the compounds of the presently disclosed host matter canbe combined with various sweetening agents, flavoring agents, coloringagents, emulsifying agents and/or suspending agents, as well as suchdiluents as water, ethanol, propylene glycol, glycerin and various likecombinations thereof.

In yet another embodiment of the host matter described herein, there areprovided injectable, stable, sterile formulations comprising an activecompound as described herein, or a salt thereof, in a unit dosage formin a sealed container. The compound or salt is provided in the form of alyophilizate, which is capable of being reconstituted with a suitablepharmaceutically acceptable carrier to form liquid formulation suitablefor injection thereof into a host. When the compound or salt issubstantially water-insoluble, a sufficient amount of emulsifying agent,which is physiologically acceptable, can be employed in sufficientquantity to emulsify the compound or salt in an aqueous carrier.Particularly useful emulsifying agents include phosphatidyl cholines andlecithin.

Additional embodiments provided herein include liposomal formulations ofthe active compounds disclosed herein. The technology for formingliposomal suspensions is well known in the art. When the compound is anaqueous-soluble salt, using conventional liposome technology, the samecan be incorporated into lipid vesicles. In such an instance, due to thewater solubility of the active compound, the active compound can besubstantially entrained within the hydrophilic center or core of theliposomes. The lipid layer employed can be of any conventionalcomposition and can either contain cholesterol or can becholesterol-free. When the active compound of interest iswater-insoluble, again employing conventional liposome formationtechnology, the salt can be substantially entrained within thehydrophobic lipid bilayer that forms the structure of the liposome. Ineither instance, the liposomes that are produced can be reduced in size,as through the use of standard sonication and homogenization techniques.The liposomal formulations comprising the active compounds disclosedherein can be lyophilized to produce a lyophilizate, which can bereconstituted with a pharmaceutically acceptable carrier, such as water,to regenerate a liposomal suspension.

Pharmaceutical formulations also are provided which are suitable foradministration as an aerosol by inhalation. These formulations comprisea solution or suspension of a desired compound described herein or asalt thereof, or a plurality of solid particles of the compound or salt.The desired formulations can be placed in a small chamber and nebulized.Nebulization can be accomplished by compressed air or by ultrasonicenergy to form a plurality of liquid droplets or solid particlescomprising the compounds or salts. The liquid droplets or solidparticles may for example have a particle size in the range of about 0.5to about 10 microns, and optionally from about 0.5 to about 5 microns.In one embodiment, the solid particles provide for controlled releasethrough the use of a degradable polymer. The solid particles can beobtained by processing the solid compound or a salt thereof, in anyappropriate manner known in the art, such as by micronization.Optionally, the size of the solid particles or droplets can be fromabout 1 to about 2 microns. In this respect, commercial nebulizers areavailable to achieve this purpose. The compounds can be administered viaan aerosol suspension of respirable particles in a manner set forth inU.S. Pat. No. 5,628,984, the disclosure of which is incorporated hereinby reference in its entirety.

Pharmaceutical formulations also are provided which provide a controlledrelease of a compound described herein, including through the use of adegradable polymer, as known in the art.

When the pharmaceutical formulations suitable for administration as anaerosol is in the form of a liquid, the formulations can comprise awater-soluble active compound in a carrier that comprises water. Asurfactant can be present, which lowers the surface tension of theformulations sufficiently to result in the formation of droplets withinthe desired size range when hosted to nebulization.

The term “pharmaceutically acceptable salts” as used herein refers tothose salts which are, within the scope of sound medical judgment,suitable for use in contact with hosts (e.g., human hosts) without unduetoxicity, irritation, allergic response, and the like, commensurate witha reasonable benefit/risk ratio, and effective for their intended use,as well as the zwitterionic forms, where possible, of the compounds ofthe presently disclosed host matter.

Thus, the term “salts” refers to the relatively non-toxic, inorganic andorganic acid addition salts of the presently disclosed compounds. Thesesalts can be prepared during the final isolation and purification of thecompounds or by separately reacting the purified compound in its freebase form with a suitable organic or inorganic acid and isolating thesalt thus formed. Basic compounds are capable of forming a wide varietyof different salts with various inorganic and organic acids. Acidaddition salts of the basic compounds are prepared by contacting thefree base form with a sufficient amount of the desired acid to producethe salt in the conventional manner. The free base form can beregenerated by contacting the salt form with a base and isolating thefree base in the conventional manner. The free base forms may differfrom their respective salt forms in certain physical properties such assolubility in polar solvents. Pharmaceutically acceptable base additionsalts may be formed with metals or amines, such as alkali and alkalineearth metal hydroxides, or of organic amines. Examples of metals used ascations, include, but are not limited to, sodium, potassium, magnesium,calcium, and the like. Examples of suitable amines include, but are notlimited to, N,N′-dibenzylethylenediamine, chloroprocaine, choline,diethanolamine, ethylenediamine, N-methylglucamine, and procaine. Thebase addition salts of acidic compounds are prepared by contacting thefree acid form with a sufficient amount of the desired base to producethe salt in the conventional manner. The free acid form can beregenerated by contacting the salt form with an acid and isolating thefree acid in a conventional manner. The free acid forms may differ fromtheir respective salt forms somewhat in certain physical properties suchas solubility in polar solvents.

Salts can be prepared from inorganic acids sulfate, pyrosulfate,bisulfate, sulfite, bisulfite, nitrate, phosphate,monohydrogenphosphate, dihydrogenphosphate, metaphosphate,pyrophosphate, chloride, bromide, iodide such as hydrochloric, nitric,phosphoric, sulfuric, hydrobromic, hydriodic, phosphorus, and the like.Representative salts include the hydrobromide, hydrochloride, sulfate,bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate,stearate, laurate, borate, benzoate, lactate, phosphate, tosylate,citrate, maleate, fumarate, succinate, tartrate, naphthylate mesylate,glucoheptonate, lactobionate, laurylsulphonate and isethionate salts,and the like. Salts can also be prepared from organic acids, such asaliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoicacids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids,aliphatic and aromatic sulfonic acids, etc. and the like. Representativesalts include acetate, propionate, caprylate, isobutyrate, oxalate,malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate,benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate,benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate,maleate, tartrate, methanesulfonate, and the like. Pharmaceuticallyacceptable salts can include cations based on the alkali and alkalineearth metals, such as sodium, lithium, potassium, calcium, magnesium andthe like, as well as non-toxic ammonium, quaternary ammonium, and aminecations including, but not limited to, ammonium, tetramethylammonium,tetraethylammonium, methylamine, dimethylamine, trimethylamine,triethylamine, ethylamine, and the like. Also contemplated are the saltsof amino acids such as arginate, gluconate, galacturonate, and the like.See, for example, Berge et al., J. Pharm. Sci., 1977, 66, 1-19, which isincorporated herein by reference.

Preferably, sterile injectable suspensions are formulated according totechniques known in the art using suitable carriers, dispersing orwetting agents and suspending agents. The sterile injectable formulationcan also be a sterile injectable solution or a suspension in a nontoxicparenterally acceptable diluent or solvent. Among the acceptablevehicles and solvents that can be employed are water, Ringer's solutionand isotonic sodium chloride solution. In addition, sterile, fixed oils,fatty esters or polyols are conventionally employed as solvents orsuspending media. In addition, parenteral administration can involve theuse of a slow release or sustained release system such that a constantlevel of dosage is maintained.

Preparations according to the disclosure for parenteral administrationinclude sterile aqueous or non-aqueous solutions, suspensions, oremulsions. Examples of non-aqueous solvents or vehicles are propyleneglycol, polyethylene glycol, vegetable oils, such as olive oil and cornoil, gelatin, and injectable organic esters such as ethyl oleate. Suchdosage forms can also contain adjuvants such as preserving, wetting,emulsifying, and dispersing agents. They can be sterilized by, forexample, filtration through a bacteria retaining filter, byincorporating sterilizing agents into the compositions, by irradiatingthe compositions, or by heating the compositions. They can also bemanufactured using sterile water, or some other sterile injectablemedium, immediately before use.

Sterile injectable solutions are prepared by incorporating one or moreof the compounds of the disclosure in the required amount in theappropriate solvent with various of the other ingredients enumeratedabove, as required, followed by filtered sterilization. Generally,dispersions are prepared by incorporating the various sterilized activeingredients into a sterile vehicle which contains the basic dispersionmedium and the required other ingredients from those enumerated above.In the case of sterile powders for the preparation of sterile injectablesolutions, the preferred methods of preparation are vacuum-drying andfreeze-drying techniques which yield a powder of the active ingredientplus any additional desired ingredient from a previouslysterile-filtered solution thereof. Thus, for example, a parenteralcomposition suitable for administration by injection is prepared bystirring 1.5% by weight of active ingredient in 10% by volume propyleneglycol and water. The solution is made isotonic with sodium chloride andsterilized.

Formulations suitable for rectal administration are typically presentedas unit dose suppositories. These may be prepared by admixing the activedisclosed compound with one or more conventional solid carriers, forexample, cocoa butter, and then shaping the resulting mixture.

Formulations suitable for topical application to the skin preferablytake the form of an ointment, cream, lotion, paste, gel, spray, aerosol,or oil. Carriers which may be used include petroleum jelly, lanoline,polyethylene glycols, alcohols, transdermal enhancers, and combinationsof two or more thereof.

Formulations suitable for transdermal administration may be presented asdiscrete patches adapted to remain in intimate contact with theepidermis of the recipient for a prolonged period of time. Formulationssuitable for transdermal administration may also be delivered byiontophoresis (see, for example, Pharmaceutical Research 3 (6):318(1986)) and typically take the form of an optionally buffered aqueoussolution of the active compound. In one embodiment, microneedle patchesor devices are provided for delivery of drugs across or into biologicaltissue, particularly the skin. The microneedle patches or devices permitdrug delivery at clinically relevant rates across or into skin or othertissue barriers, with minimal or no damage, pain, or irritation to thetissue.

Formulations suitable for administration to the lungs can be deliveredby a wide range of passive breath driven and active power drivensingle/-multiple dose dry powder inhalers (DPI). The devices mostcommonly used for respiratory delivery include nebulizers, metered-doseinhalers, and dry powder inhalers. Several types of nebulizers areavailable, including jet nebulizers, ultrasonic nebulizers, andvibrating mesh nebulizers. Selection of a suitable lung delivery devicedepends on parameters, such as nature of the drug and its formulation,the site of action, and pathophysiology of the lung.

Additional non-limiting examples of drug delivery devices and methodsinclude, for example, US20090203709 titled “Pharmaceutical Dosage FormFor Oral Administration Of Tyrosine Kinase Inhibitor” (AbbottLaboratories); US20050009910 titled “Delivery of an active drug to theposterior part of the eye via subconjunctival or periocular delivery ofa prodrug”, US 20130071349 titled “Biodegradable polymers for loweringintraocular pressure”, U.S. Pat. No. 8,481,069 titled “Tyrosine kinasemicrospheres”, U.S. Pat. No. 8,465,778 titled “Method of making tyrosinekinase microspheres”, U.S. Pat. No. 8,409,607 titled “Sustained releaseintraocular implants containing tyrosine kinase inhibitors and relatedmethods”, U.S. Pat. No. 8,512,738 and US 2014/0031408 titled“Biodegradable intravitreal tyrosine kinase implants”, US 2014/0294986titled “Microsphere Drug Delivery System for Sustained IntraocularRelease”, U.S. Pat. No. 8,911,768 titled “Methods For TreatingRetinopathy With Extended Therapeutic Effect” (Allergan, Inc.); U.S.Pat. No. 6,495,164 titled “Preparation of injectable suspensions havingimproved injectability” (Alkermes Controlled Therapeutics, Inc.); WO2014/047439 titled “Biodegradable Microcapsules Containing FillingMaterial” (Akina, Inc.); WO 2010/132664 titled “Compositions And MethodsFor Drug Delivery” (Baxter International Inc. Baxter Healthcare SA);US20120052041 titled “Polymeric nanoparticles with enhanced drug loadingand methods of use thereof” (The Brigham and Women's Hospital, Inc.);US20140178475, US20140248358, and US20140249158 titled “TherapeuticNanoparticles Comprising a Therapeutic Agent and Methods of Making andUsing Same” (BIND Therapeutics, Inc.); U.S. Pat. No. 5,869,103 titled“Polymer microparticles for drug delivery” (Danbiosyst UK Ltd.); U.S.Pat. No. 8,628,801 titled “Pegylated Nanoparticles” (Universidad deNavarra); US2014/0107025 titled “Ocular drug delivery system” (JadeTherapeutics, LLC); U.S. Pat. No. 6,287,588 titled “Agent deliveringsystem comprised of microparticle and biodegradable gel with an improvedreleasing profile and methods of use thereof”, U.S. Pat. No. 6,589,549titled “Bioactive agent delivering system comprised of microparticleswithin a biodegradable to improve release profiles” (Macromed, Inc.);U.S. Pat. Nos. 6,007,845 and 5,578,325 titled “Nanoparticles andmicroparticles of non-linear hydrophilic hydrophobic multiblockcopolymers” (Massachusetts Institute of Technology); US20040234611,US20080305172, US20120269894, and US20130122064 titled “Ophthalmic depotformulations for periocular or subconjunctival administration (NovartisAg); U.S. Pat. No. 6,413,539 titled “Block polymer” (Poly-Med, Inc.); US20070071756 titled “Delivery of an agent to ameliorate inflammation”(Peyman); US 20080166411 titled “Injectable Depot Formulations AndMethods For Providing Sustained Release Of Poorly Soluble DrugsComprising Nanoparticles” (Pfizer, Inc.); U.S. Pat. No. 6,706,289 titled“Methods and compositions for enhanced delivery of bioactive molecules”(PR Pharmaceuticals, Inc.); and U.S. Pat. No. 8,663,674 titled“Microparticle containing matrices for drug delivery” (Surmodics).

VII. Combination Therapy

The disclosed compounds of Formula I, Formula II, Formula III, orFormula IV can be used in an effective amount alone or in combinationwith another compound of the present invention or another bioactiveagent to treat a host such as a human with a disorder as describedherein.

The disclosed compounds described herein can be used in an effectiveamount alone or in combination with another compound of the presentinvention or another bioactive agent to treat a host such as a humanwith a disorder as described herein.

The term “bioactive agent” is used to describe an agent, other than theselected compound according to the present invention, which can be usedin combination or alternation with a compound of the present inventionto achieve a desired result of therapy. In one embodiment, the compoundof the present invention and the bioactive agent are administered in amanner that they are active in vivo during overlapping time periods, forexample, have time-period overlapping Cmax, Tmax, AUC or otherpharmacokinetic parameter. In another embodiment, the compound of thepresent invention and the bioactive agent are administered to a host inneed thereof that do not have overlapping pharmacokinetic parameter,however, one has a therapeutic impact on the therapeutic efficacy of theother.

In one aspect of this embodiment, the bioactive agent is an immunemodulator, including but not limited to a checkpoint inhibitor,including as non-limiting examples, a PD-1 inhibitor, PD-L1 inhibitor,PD-L2 inhibitor, CTLA-4 inhibitor, LAG-3 inhibitor, TIM-3 inhibitor,V-domain Ig suppressor of T-cell activation (VISTA) inhibitors, smallmolecule, peptide, nucleotide, or other inhibitor. In certain aspects,the immune modulator is an antibody, such as a monoclonal antibody.

PD-1 inhibitors that blocks the interaction of PD-1 and PD-L1 by bindingto the PD-1 receptor, and in turn inhibit immune suppression include,for example, nivolumab (Opdivo), pembrolizumab (Keytruda), pidilizumab,AMP-224 (AstraZeneca and MedImmune), PF-06801591 (Pfizer), MEDI0680(AstraZeneca), PDR001 (Novartis), REGN2810 (Regeneron), SHR-12-1(Jiangsu Hengrui Medicine Company and Incyte Corporation), TSR-042(Tesaro), and the PD-LN/VISTA inhibitor CA-170 (Curis Inc.). PD-L1inhibitors that block the interaction of PD-1 and PD-L1 by binding tothe PD-L1 receptor, and in turn inhibits immune suppression, include forexample, atezolizumab (Tecentriq), durvalumab (AstraZeneca andMedImmune), KN035 (Alphamab), and BMS-936559 (Bristol-Myers Squibb).CTLA-4 checkpoint inhibitors that bind to CTLA-4 and inhibits immunesuppression include, but are not limited to, ipilimumab, tremelimumab(AstraZeneca and MedImmune), AGEN1884 and AGEN2041 (Agenus). LAG-3checkpoint inhibitors, include, but are not limited to, BMS-986016(Bristol-Myers Squibb), GSK2831781 (GlaxoSmithKline), IMP321 (PrimaBioMed), LAG525 (Novartis), and the dual PD-1 and LAG-3 inhibitor MGD013(MacroGenics). An example of a TIM-3 inhibitor is TSR-022 (Tesaro).

In yet another embodiment, one of the active compounds described hereincan be administered in an effective amount for the treatment of abnormaltissue of the female reproductive system such as breast, ovarian,endometrial, or uterine cancer, in combination or alternation with aneffective amount of an estrogen inhibitor including but not limited to aSERM (selective estrogen receptor modulator), a SERD (selective estrogenreceptor degrader), a complete estrogen receptor degrader, or anotherform of partial or complete estrogen antagonist or agonist. Partialanti-estrogens like raloxifene and tamoxifen retain some estrogen-likeeffects, including an estrogen-like stimulation of uterine growth, andalso, in some cases, an estrogen-like action during breast cancerprogression which actually stimulates tumor growth. In contrast,fulvestrant, a complete anti-estrogen, is free of estrogen-like actionon the uterus and is effective in tamoxifen-resistant tumors.Non-limiting examples of anti-estrogen compounds are provided in WO2014/19176 assigned to Astra Zeneca, WO2013/090921, WO 2014/203129, WO2014/203132, and US2013/0178445 assigned to Olema Pharmaceuticals, andU.S. Pat. Nos. 9,078,871, 8,853,423, and 8,703, 810, as well as US2015/0005286, WO 2014/205136, and WO 2014/205138. Additionalnon-limiting examples of anti-estrogen compounds include: SERMS such asanordrin, bazedoxifene, broparestriol, chlorotrianisene, clomiphenecitrate, cyclofenil, lasofoxifene, ormeloxifene, raloxifene, tamoxifen,toremifene, and fulvestrant; aromatase inhibitors such asaminoglutethimide, testolactone, anastrozole, exemestane, fadrozole,formestane, and letrozole; and antigonadotropins such as leuprorelin,cetrorelix, allylestrenol, chloromadinone acetate, cyproterone acetate,delmadinone acetate, dydrogesterone, medroxyprogesterone acetate,megestrol acetate, nomegestrol acetate, norethisterone acetate,progesterone, and spironolactone. Other estrogenic ligands that can beused according to the present invention are described in U.S. Pat. Nos.4,418,068; 5,478,847; 5,393,763; and 5,457,117, WO2011/156518, U.S. Pat.Nos. 8,455,534 and 8,299,112, 9,078,871; 8,853,423; 8,703,810; US2015/0005286; and WO 2014/205138, US2016/0175289, US2015/0258080, WO2014/191726, WO 2012/084711; WO 2002/013802; WO 2002/004418; WO2002/003992; WO 2002/003991; WO 2002/003990; WO 2002/003989; WO2002/003988; WO 2002/003986; WO 2002/003977; WO 2002/003976; WO2002/003975; WO 2006/078834; U.S. Pat. No. 6,821,989; US 2002/0128276;U.S. Pat. No. 6,777,424; US 2002/0016340; U.S. Pat. Nos. 6,326,392;6,756,401; US 2002/0013327; U.S. Pat. Nos. 6,512,002; 6,632,834; US2001/0056099; U.S. Pat. Nos. 6,583,170; 6,479,535; WO 1999/024027; U.S.Pat. No. 6,005,102; EP 0802184; U.S. Pat. Nos. 5,998,402; 5,780,497,5,880,137, WO 2012/048058 and WO 2007/087684.

In another embodiment, an active compound described herein can beadministered in an effective amount for the treatment of abnormal tissueof the male reproductive system such as prostate or testicular cancer,in combination or alternation with an effective amount of an androgen(such as testosterone) inhibitor including but not limited to aselective androgen receptor modulator, a selective androgen receptordegrader, a complete androgen receptor degrader, or another form ofpartial or complete androgen antagonist. In one embodiment, the prostateor testicular cancer is androgen-resistant. Non-limiting examples ofanti-androgen compounds are provided in WO 2011/156518 and U.S. Pat.Nos. 8,455,534 and 8,299,112. Additional non-limiting examples ofanti-androgen compounds include: enzalutamide, apalutamide, cyproteroneacetate, chlormadinone acetate, spironolactone, canrenone, drospirenone,ketoconazole, topilutamide, abiraterone acetate, and cimetidine.

In one embodiment, the bioactive agent is an ALK inhibitor. Examples ofALK inhibitors include but are not limited to Crizotinib, Alectinib,ceritinib, TAE684 (NVP-TAE684), GSK1838705A, AZD3463, ASP3026,PF-06463922, entrectinib (RXDX-101), and AP26113.

In one embodiment, the bioactive agent is an EGFR inhibitor. Examples ofEGFR inhibitors include erlotinib (Tarceva), gefitinib (Iressa),afatinib (Gilotrif), rociletinib (CO-1686), osimertinib (Tagrisso),olmutinib (Olita), naquotinib (ASP8273), nazartinib (EGF816),PF-06747775 (Pfizer), icotinib (BPI-2009), neratinib (HKI-272; PB272);avitinib (AC0010), EAI045, tarloxotinib (TH-4000; PR-610), PF-06459988(Pfizer), tesevatinib (XL647; EXEL-7647; KD-019), transtinib, WZ-3146,WZ8040, CNX-2006, and dacomitinib (PF-00299804; Pfizer).

In one embodiment, the bioactive agent is an HER-2 inhibitor. Examplesof HER-2 inhibitors include trastuzumab, lapatinib, ado-trastuzumabemtansine, and pertuzumab.

In one embodiment, the bioactive agent is a CD20 inhibitor. Examples ofCD20 inhibitors include obinutuzumab, rituximab, fatumumab, ibritumomab,tositumomab, and ocrelizumab.

In one embodiment, the bioactive agent is a JAK3 inhibitor. Examples ofJAK3 inhibitors include tasocitinib.

In one embodiment, the bioactive agent is a BCL-2 inhibitor. Examples ofBCL-2 inhibitors include venetoclax, ABT-199(4-[4-[[2-(4-Chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl]-N-[[3-nitro-4-[[(tetrahydro-2H-pyran-4-yl)methyl]amino]phenyl]sulfonyl]-2-[(1H-pyrrolo[2,3-b]pyridin-5-yl)oxy]benzamide),ABT-737(4-[4-[[2-(4-chlorophenyl)phenyl]methyl]piperazin-1-yl]-N-[4-[[(2R)-4-(dimethylamino)-1-phenylsulfanylbutan-2-yl]amino]-3-nitrophenyl]sulfonylbenzamide) (navitoclax), ABT-263((R)-4-(4-((4′-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((4-morpholino-1-(phenylthio)butan-2-yl)amino)-3((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide),GX15-070 (obatoclax mesylate,(2Z)-2-[(5Z)-5-[(3,5-dimethyl-1H-pyrrol-2-yl)methylidene]-4-methoxypyrrol-2-ylidene]indole;methanesulfonic acid))), 2-methoxy-antimycin A3, YC137(4-(4,9-dioxo-4,9-dihydronaphtho[2,3-d]thiazol-2-ylamino)-phenyl ester),pogosin, ethyl2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate,Nilotinib-d3, TW-37(N-[4-[[2-(1,1-Dimethylethyl)phenyl]sulfonyl]phenyl]-2,3,4-trihydroxy-5-[[2-(1-methylethyl)phenyl]methyl]benzamide),Apogossypolone (ApoG2), HA14-1, AT101, sabutoclax, gambogic acid, orG3139 (Oblimersen).

In one aspect, a treatment regimen is provided comprising theadministration of a compound of Formula I, Formula II, Formula III, orFormula IV in combination with at least one additional chemotherapeuticagent. The combinations disclosed herein can be administered forbeneficial, additive, or synergistic effect in the treatment of abnormalcellular proliferative disorders.

In specific embodiments, the treatment regimen includes theadministration of a compound of Formula I, Formula II, Formula III, orFormula IV in combination with at least one kinase inhibitor. In oneembodiment, the at least one kinase inhibitor is selected from aphosphoinositide 3-kinase (PI3K) inhibitor, a Bruton's tyrosine kinase(BTK) inhibitor, or a spleen tyrosine kinase (Syk) inhibitor, or acombination thereof.

PI3k inhibitors that may be used in the present invention are wellknown. Examples of PI3 kinase inhibitors include but are not limited toWortmannin, demethoxyviridin, perifosine, idelalisib, Pictilisib,Palomid 529, ZSTK474, PWT33597, CUDC-907, and AEZS-136, duvelisib,GS-9820, BKM120, GDC-0032 (Taselisib),(2-[4-[2-(2-Isopropyl-5-methyl-1,2,4-triazol-3-yl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepin-9-yl]pyrazol-1-yl]-2-methylpropanamide),MLN-1117 ((2R)-1-Phenoxy-2-butanyl hydrogen (S)-methylphosphonate; orMethyl(oxo) {[(2R)-1-phenoxy-2-butanyl]oxy}phosphonium)), BYL-719((2S)—N1-[4-Methyl-5-[2-(2,2,2-trifluoro-1,1-dimethylethyl)-4-pyridinyl]-2-thiazolyl]-1,2-pyrrolidinedicarboxamide),GSK2126458(2,4-Difluoro-N-{2-(methyloxy)-5-[4-(4-pyridazinyl)-6-quinolinyl]-3-pyridinyl}benzenesulfonamide)(omipalisib), TGX-221((+)-7-Methyl-2-(morpholin-4-yl)-9-(1-phenylaminoethyl)-pyrido[1,2-a]-pyrimidin-4-one),GSK2636771(2-Methyl-1-(2-methyl-3-(trifluoromethyl)benzyl)-6-morpholino-1H-benzo[d]imidazole-4-carboxylicacid dihydrochloride), KIN-193((R)-2-((1-(7-methyl-2-morpholino-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoicacid), TGR-1202/RP5264, GS-9820((S)-1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-mohydroxypropan-1-one),GS-1101(5-fluoro-3-phenyl-2-([S)]-1-[9H-purin-6-ylamino]-propyl)-3H-quinazolin-4-one),AMG-319, GSK-2269557, SAR245409(N-(4-(N-(3-((3,5-dimethoxyphenyl)amino)quinoxalin-2-yl)sulfamoyl)phenyl)-3-methoxy-4methylbenzamide), BAY80-6946(2-amino-N-(7-methoxy-8-(3-morpholinopropoxy)-2,3-dihydroimidazo[1,2-c]quinaz),AS 252424(5-[1-[5-(4-Fluoro-2-hydroxy-phenyl)-furan-2-yl]-meth-(Z)-ylidene]-thiazolidine-2,4-dione),CZ 24832(5-(2-amino-8-fluoro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-N-tert-butylpyridine-3-sulfonamide),Buparlisib(5-[2,6-Di(4-morpholinyl)-4-pyrimidinyl]-4-(trifluoromethyl)-2-pyridinamine),GDC-0941(2-(1H-Indazol-4-yl)-6-[[4-(methylsulfonyl)-1-piperazinyl]methyl]-4-(4-morpholinyl)thieno[3,2-d]pyrimidine),GDC-0980((S)-1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one (also known as RG7422)),SF1126((8S,14S,17S)-14-(carboxymethyl)-8-(3-guanidinopropyl)-17-(hydroxymethyl)-3,6,9,12,15-pentaoxo-1-(4-(4-oxo-8-phenyl-4H-chromen-2-yl)morpholino-4-ium)-2-oxa-7,10,13,16-tetraazaoctadecan-18-oate),PF-05212384(N-[4-[[4-(Dimethylamino)-1-piperidinyl]carbonyl]phenyl]-N′-[4-(4,6-di-4-morpholinyl-1,3,5-triazin-2-yl)phenyl]urea)(gedatolisib), LY3023414, BEZ235(2-Methyl-2-{4-[3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl]phenyl}propanenitrile)(dactolisib), XL-765(N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-3-methoxy-4-methylbenzamide),and GSK1059615(5-[[4-(4-Pyridinyl)-6-quinolinyl]methylene]-2,4-thiazolidenedione),PX886([(3aR,6E,9S,9aR,10R,11aS)-6-[[bis(prop-2-enyl)amino]methylidene]-5-hydroxy-9-(methoxymethyl)-9a,11a-dimethyl-1,4,7-trioxo-2,3,3a,9,10,11-hexahydroindeno[4,5h]isochromen-10-yl]acetate (also known as sonolisib)) LY294002, AZD8186, PF-4989216,pilaralisib, GNE-317, PI-3065, PI-103, NU7441 (KU-57788), HS 173,VS-5584 (SB2343), CZC24832, TG100-115, A66, YM201636, CAY10505, PIK-75,PIK-93, AS-605240, BGT226 (NVP-BGT226), AZD6482, voxtalisib, alpelisib,IC-87114, TGI100713, CH5132799, PKI-402, copanlisib (BAY 80-6946), XL147, PIK-90, PIK-293, PIK-294, 3-MA (3-methyladenine), AS-252424,AS-604850, apitolisib (GDC-0980; RG7422), and the structure described inWO2014/071109.

In one embodiment, the compound of Formula I, Formula II, Formula III,or Formula IV is combined in a single dosage form with the PIk3inhibitor.

BTK inhibitors for use in the present invention are well known. Examplesof BTK inhibitors include ibrutinib (also known asPCI-32765)(Imbruvica™)(1-[(3R)-3-[4-amino-3-(4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]prop-2-en-1-one),dianilinopyrimidine-based inhibitors such as AVL-101 and AVL-291/292(N-(3-((5-fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide)(Avila Therapeutics) (see US Patent Publication No 2011/0117073,incorporated herein in its entirety), Dasatinib([N-(2-chloro-6-methylphenyl)-2-(6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide],LFM-A13 (alpha-cyano-beta-hydroxy-beta-methyl-N-(2,5-ibromophenyl)propenamide), GDC-0834([R—N-(3-(6-(4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide],CGI-5604-(tert-butyl)-N-(3-(8-(phenylamino)imidazo[1,2-a]pyrazin-6-yl)phenyl)benzamide,CGI-1746(4-(tert-butyl)-N-(2-methyl-3-(4-methyl-6-((4-(morpholine-4-carbonyl)phenyl)amino)-5-oxo-4,5-dihydropyrazin-2-yl)phenyl)benzamide),CNX-774(4-(4-((4-((3-acrylamidophenyl)amino)-5-fluoropyrimidin-2-yl)amino)phenoxy)-N-methylpicolinamide),CTA056(7-benzyl-1-(3-(piperidin-1-yl)propyl)-2-(4-(pyridin-4-yl)phenyl)-1H-imidazo[4,5-g]quinoxalin-6(5H)-one),GDC-0834((R)—N-(3-(6-((4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl)amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide),GDC-0837((R)—N-(3-(6-((4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl)amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide),HM-71224, ACP-196, ONO-4059 (Ono Pharmaceuticals), PRT062607(4-((3-(2H-1,2,3-triazol-2-yl)phenyl)amino)-2-(((1R,2S)-2-aminocyclohexyl)amino)pyrimidine-5-carboxamidehydrochloride), QL-47(1-(1-acryloylindolin-6-yl)-9-(1-methyl-1H-pyrazol-4-yl)benzo[h][1,6]naphthyridin-2(1H)-one),and RN486(6-cyclopropyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methylpiperazin-1-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-2H-isoquinolin-1-one),and other molecules capable of inhibiting BTK activity, for examplethose BTK inhibitors disclosed in Akinleye et ah, Journal of Hematology& Oncology, 2013, 6:59, the entirety of which is incorporated herein byreference. In one embodiment, the compound of Formula I, Formula II,Formula III, or Formula IV is combined in a single dosage form with theBTK inhibitor.

Syk inhibitors for use in the present invention are well known, andinclude, for example, Cerdulatinib(4-(cyclopropylamino)-2-((4-(4-(ethylsulfonyl)piperazin-1-yl)phenyl)amino)pyrimidine-5-carboxamide),entospletinib(6-(1H-indazol-6-yl)-N-(4-morpholinophenyl)imidazo[1,2-a]pyrazin-8-amine),fostamatinib([6-({5-Fluoro-2-[(3,4,5-trimethoxyphenyl)amino]-4-pyrimidinyl)}amino)-2,2-dimethyl-3-oxo-2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazin-4-yl]methyldihydrogen phosphate), fostamatinib disodium salt (sodium(6-((5-fluoro-2-((3,4,5-trimethoxyphenyl)amino)pyrimidin-4-yl)amino)-2,2-dimethyl-3-oxo-2H-pyrido[3,2-b][1,4]oxazin-4(3H)-yl)methylphosphate), BAY 61-3606(2-(7-(3,4-Dimethoxyphenyl)-imidazo[1,2-c]pyrimidin-5-ylamino)-nicotinamideHCl), RO9021(6-[(1R,2S)-2-Amino-cyclohexylamino]-4-(5,6-dimethyl-pyridin-2-ylamino)-pyridazine-3-carboxylicacid amide), imatinib (Gleevac;4-[(4-methylpiperazin-1-yl)methyl]-N-(4-methyl-3-{[4-(pyridin-3-yl)pyrimidin-2-yl]amino}phenyl)benzamide),staurosporine, GSK143(2-(((3R,4R)-3-aminotetrahydro-2H-pyran-4-yl)amino)-4-(p-tolylamino)pyrimidine-5-carboxamide),PP2(1-(tert-butyl)-3-(4-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine),PRT-060318(2-(((1R,2S)-2-aminocyclohexyl)amino)-4-(m-tolylamino)pyrimidine-5-carboxamide),PRT-062607(4-((3-(2H-1,2,3-triazol-2-yl)phenyl)amino)-2-(((1R,2S)-2-aminocyclohexyl)amino)pyrimidine-5-carboxamidehydrochloride), R112(3,3′-((5-fluoropyrimidine-2,4-diyl)bis(azanediyl))diphenol), R348(3-Ethyl-4-methylpyridine), R406 (6-((5-fluoro-2-((3,4,5-trimethoxyphenyl)amino)pyrimidin-4-yl)amino)-2,2-dimethyl-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one),piceatannol (3-Hydroxyresveratol), YM193306 (see Singh et al. Discoveryand Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med.Chem. 2012, 55, 3614-3643), 7-azaindole, piceatannol, ER-27319 (seeSingh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK)Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 incorporated in itsentirety herein), Compound D (see Singh et al. Discovery and Developmentof Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55,3614-3643 incorporated in its entirety herein), PRT060318 (see Singh etal. Discovery and Development of Spleen Tyrosine Kinase (SYK)Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 incorporated in itsentirety herein), luteolin (see Singh et al. Discovery and Developmentof Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55,3614-3643 incorporated in its entirety herein), apigenin (see Singh etal. Discovery and Development of Spleen Tyrosine Kinase (SYK)Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 incorporated in itsentirety herein), quercetin (see Singh et al. Discovery and Developmentof Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55,3614-3643 incorporated in its entirety herein), fisetin (see Singh etal. Discovery and Development of Spleen Tyrosine Kinase (SYK)Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 incorporated in itsentirety herein), myricetin (see Singh et al. Discovery and Developmentof Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55,3614-3643 incorporated in its entirety herein), morin (see Singh et al.Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J.Med. Chem. 2012, 55, 3614-3643 incorporated in its entirety herein). Inone embodiment, the compound of Formula I, Formula II, Formula III, orFormula IV is combined in a single dosage form with the Syk inhibitor.

In one embodiment, the at least one additional chemotherapeutic agent isa protein cell death-1 (PD-1) inhibitor. PD-1 inhibitors are known inthe art, and include, for example, nivolumab (BMS), pembrolizumab(Merck), pidilizumab (CureTech/Teva), AMP-244 (Amplimmune/GSK),BMS-936559 (BMS), and MEDI4736 (Roche/Genentech). In one embodiment, thecompound of Formula I, Formula II, Formula III, or Formula IV iscombined in a single dosage form with the PD-1 inhibitor.

In one embodiment, the at least one additional chemotherapeutic agent isa B-cell lymphoma 2 (Bcl-2) protein inhibitor. BCL-2 inhibitors areknown in the art, and include, for example, ABT-199(4-[4-[[2-(4-Chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl]-N-[[3-nitro-4-[[(tetrahydro-2H-pyran-4-yl)methyl]amino]phenyl]sulfonyl]-2-[(1H-pyrrolo[2,3-b]pyridin-5-yl)oxy]benzamide),ABT-737(4-[4-[[2-(4-chlorophenyl)phenyl]methyl]piperazin-1-yl]-N-[4-[[(2R)-4-(dimethylamino)-1-phenylsulfanylbutan-2-yl]amino]-3-nitrophenyl]sulfonylbenzamide), ABT-263((R)-4-(4-((4′-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((4-morpholino-1-(phenylthio)butan-2-yl)amino)-3((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide),GX15-070 (obatoclax mesylate,(2Z)-2-[(5Z)-5-[(3,5-dimethyl-1H-pyrrol-2-yl)methylidene]-4-methoxypyrrol-2-ylidene]indole;methanesulfonic acid))), 2-methoxy-antimycin A3, YC137(4-(4,9-dioxo-4,9-dihydronaphtho[2,3-d]thiazol-2-ylamino)-phenyl ester),pogosin, ethyl2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate,Nilotinib-d3, TW-37(N-[4-[[2-(1,1-Dimethylethyl)phenyl]sulfonyl]phenyl]-2,3,4-trihydroxy-5-[[2-(1-methylethyl)phenyl]methyl]benzamide),Apogossypolone (ApoG2), or G3139 (Oblimersen). In one embodiment, thecompound of Formula I, Formula II, Formula III, or Formula IV iscombined in a single dosage form with the at least one BCL-2 inhibitor.

In one embodiment, a combination described herein can be furthercombined with an additional therapeutic to treat the cancer. The secondtherapy can be an immunotherapy. As discussed in more detail below, thecompound of Formula I, Formula II, Formula III, or Formula IV can beconjugated to an antibody, radioactive agent, or other targeting agentthat directs the compound to the diseased or abnormally proliferatingcell. In another embodiment, the combination is used in combination withanother pharmaceutical or a biologic agent (for example an antibody) toincrease the efficacy of treatment with a combined or a synergisticapproach. In an embodiment, combination can be used with T-cellvaccination, which typically involves immunization with inactivatedautoreactive T cells to eliminate a cancer cell population as describedherein. In another embodiment, the combination is used in combinationwith a bispecific T-cell Engager (BiTE), which is an antibody designedto simultaneously bind to specific antigens on endogenous T cells andcancer cells as described herein, linking the two types of cells.

In one embodiment, the bioactive agent is a MEK inhibitor. MEKinhibitors are well known, and include, for example,trametinib/GSKl120212(N-(3-{3-Cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H-yl}phenyl)acetamide),selumetinib(6-(4-bromo-2-chloroanilino)-7-fluoro-N-(2-hydroxyethoxy)-3-methylbenzimidazole-5-carboxamide),pimasertib/AS703026/MSC 1935369((S)—N-(2,3-dihydroxypropyl)-3-((2-fluoro-4-iodophenyl)amino)isonicotinamide),XL-518/GDC-0973(1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2S)-piperidin-2-yl]azetidin-3-ol),refametinib/BAY869766/RDEAl 19(N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide),PD-0325901(N-[(2R)-2,3-Dihydroxypropoxy]-3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-benzamide),TAK733((R)-3-(2,3-Dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione),MEK162/ARRY438162(5-[(4-Bromo-2-fluorophenyl)amino]-4-fluoro-N-(2-hydroxyethoxy)-1-methyl-1H-benzimidazole-6-carboxamide),R05126766(3-[[3-Fluoro-2-(methylsulfamoylamino)-4-pyridyl]methyl]-4-methyl-7-pyrimidin-2-yloxychromen-2-one),WX-554, R04987655/CH4987655(3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-5-((3-oxo-1,2-oxazinan-2yl)methyl)benzamide),or AZD8330 (2-((2-fluoro-4-iodophenyl)amino)-N-(2hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide),U0126-EtOH, PD184352 (CI-1040), GDC-0623, BI-847325, cobimetinib,PD98059, BIX 02189, BIX 02188, binimetinib, SL-327, TAK-733, PD318088.

In one embodiment, the bioactive agent is a Raf inhibitor. Rafinhibitors are known and include, for example, Vemurafinib(N-[3-[[5-(4-Chlorophenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]carbonyl]-2,4-difluorophenyl]-1-propanesulfonamide),sorafenib tosylate(4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]phenoxy]-N-methylpyridine-2-carboxamide;4-methylbenzenesulfonate), AZ628(3-(2-cyanopropan-2-yl)-N-(4-methyl-3-(3-methyl-4-oxo-3,4-dihydroquinazolin-6-ylamino)phenyl)benzamide),NVP-BHG712(4-methyl-3-(1-methyl-6-(pyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino)-N-(3-(trifluoromethyl)phenyl)benzamide),RAF-265(1-methyl-5-[2-[5-(trifluoromethyl)-1H-imidazol-2-yl]pyridin-4-yl]oxy-N-[4-(trifuoromethyl)phenyl]benzimidazol-2-amine),2-Bromoaldisine(2-Bromo-6,7-dihydro-1H,5H-pyrrolo[2,3-c]azepine-4,8-dione), Raf KinaseInhibitor IV(2-chloro-5-(2-phenyl-5-(pyridin-4-yl)-1H-imidazol-4-yl)phenol),Sorafenib N-Oxide(4-[4-[[[[4-Chloro-3(trifluoroMethyl)phenyl]aMino]carbonyl]aMino]phenoxy]-N-Methyl-2pyridinecarboxaMide1-Oxide), PLX-4720, dabrafenib (GSK2118436), GDC-0879, RAF265, AZ 628,SB590885, ZM336372, GW5074, TAK-632, CEP-32496, LY3009120, and GX818(Encorafenib).

In one embodiment, the additional therapy is a monoclonal antibody(MAb). Some MAbs stimulate an immune response that destroys cancercells. Similar to the antibodies produced naturally by B cells, theseMAbs “coat” the cancer cell surface, triggering its destruction by theimmune system. For example, bevacizumab targets vascular endothelialgrowth factor (VEGF), a protein secreted by tumor cells and other cellsin the tumor's microenvironment that promotes the development of tumorblood vessels. When bound to bevacizumab, VEGF cannot interact with itscellular receptor, preventing the signaling that leads to the growth ofnew blood vessels. Similarly, cetuximab and panitumumab target theepidermal growth factor receptor (EGFR), and trastuzumab targets thehuman epidermal growth factor receptor 2 (HER-2). MAbs that bind to cellsurface growth factor receptors prevent the targeted receptors fromsending their normal growth-promoting signals. They may also triggerapoptosis and activate the immune system to destroy tumor cells.

Another group of cancer therapeutic MAbs are the immunoconjugates. TheseMAbs, which are sometimes called immunotoxins or antibody-drugconjugates, consist of an antibody attached to a cell-killing substance,such as a plant or bacterial toxin, a chemotherapy drug, or aradioactive molecule. The antibody latches onto its specific antigen onthe surface of a cancer cell, and the cell-killing substance is taken upby the cell. FDA-approved conjugated MAbs that work this way includeado-trastuzumab emtansine, which targets the HER-2 molecule to deliverthe drug DM1, which inhibits cell proliferation, to HER-2 expressingmetastatic breast cancer cells.

Immunotherapies with T cells engineered to recognize cancer cells viabispecific antibodies (bsAbs) or chimeric antigen receptors (CARs) areapproaches with potential to ablate both dividing and non/slow-dividingsubpopulations of cancer cells.

Bispecific antibodies, by simultaneously recognizing target antigen andan activating receptor on the surface of an immune effector cell, offeran opportunity to redirect immune effector cells to kill cancer cells.The other approach is the generation of chimeric antigen receptors byfusing extracellular antibodies to intracellular signaling domains.Chimeric antigen receptor-engineered T cells are able to specificallykill tumor cells in a MHC-independent way.

In some embodiments, the combination can be administered to the subjectin further combination with other chemotherapeutic agents. Ifconvenient, the combination described herein can be administered at thesame time as another chemotherapeutic agent, in order to simplify thetreatment regimen. In some embodiments, the combination and the otherchemotherapeutic can be provided in a single formulation. In oneembodiment, the use of the compounds described herein is combined in atherapeutic regime with other agents. Such agents may include, but arenot limited to, tamoxifen, midazolam, letrozole, bortezomib,anastrozole, goserelin, an mTOR inhibitor, a PI3 kinase inhibitors, dualmTOR-PI3K inhibitors, MEK inhibitors, RAS inhibitors, ALK inhibitors,HSP inhibitors (for example, HSP70 and HSP 90 inhibitors, or acombination thereof), BCL-2 inhibitors, apopototic inducing compounds,AKT inhibitors, including but not limited to, MK-2206, GSK690693,Perifosine, (KRX-0401), GDC-0068, Triciribine, AZD5363, Honokiol,PF-04691502, and Miltefosine, PD-1 inhibitors including but not limitedto, Nivolumab, CT-011, MK-3475, BMS936558, and AMP-514 or FLT-3inhibitors, including but not limited to, P406, Dovitinib, Quizartinib(AC220), Amuvatinib (MP-470), Tandutinib (MLN518), ENMD-2076, andKW-2449, or combinations thereof.

In one embodiment, the bioactive agent is an mTOR inhibitor. Examples ofmTOR inhibitors include but are not limited to rapamycin and itsanalogs, everolimus (Afinitor), temsirolimus, ridaforolimus, sirolimus,and deforolimus. Examples of MEK inhibitors include but are not limitedto tametinib/GSKl120212(N-(3-{3-Cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-(2H-yl}phenyl)acetamide),selumetinob(6-(4-bromo-2-chloroanilino)-7-fluoro-N-(2-hydroxyethoxy)-3-methylbenzimidazole-5-carboxamide),pimasertib/AS703026/MSC1935369((S)—N-(2,3-dihydroxypropyl)-3-((2-fluoro-4-iodophenyl)amino)isonicotinamide),XL-518/GDC-0973(1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2S)-piperidin-2-yl]azetidin-3-ol),refametinib/BAY869766/RDEAl19(N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide),PD-0325901(N-[(2R)-2,3-Dihydroxypropoxy]-3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-benzamide),TAK733((R)-3-(2,3-Dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3d]pyrimidine-4,7(3H,8H)-dione),MEK162/ARRY438162(5-[(4-Bromo-2-fluorophenyl)amino]-4-fluoro-N-(2-hydroxyethoxy)-1-methyl-1H-benzimidazole-6carboxamide), R05126766(3-[[3-Fluoro-2-(methylsulfamoylamino)-4-pyridyl]methyl]-4-methyl-7-pyrimidin-2-yloxychromen-2-one),WX-554, R04987655/CH4987655(3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-5-((3-oxo-1,2-oxazinan-2yl)methyl)benzamide), or AZD8330(2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide).

In one embodiment, the bioactive agent is a RAS inhibitor. Examples ofRAS inhibitors include but are not limited to Reolysin and siG12D LODER.

In one embodiment, the bioactive agent is an ALK inhibitor. Examples ofALK inhibitors include but are not limited to Crizotinib, AP26113, andLDK378.

In one embodiment, the bioactive agent is a HSP inhibitor. HSPinhibitors include but are not limited to Geldanamycin or17-N-Allylamino-17-demethoxygeldanamycin (17AAG), and Radicicol. In aparticular embodiment, a compound described herein is administered incombination with letrozole and/or tamoxifen. Other chemotherapeuticagents that can be used in combination with the compounds describedherein include, but are not limited to, chemotherapeutic agents that donot require cell cycle activity for their anti-neoplastic effect.

Additional bioactive compounds include, for example, everolimus,trabectedin, abraxane, TLK 286, AV-299, DN-101, pazopanib, GSK690693,RTA 744, ON 0910.Na, AZD 6244 (ARRY-142886), AMN-107, TKI-258,GSK461364, AZD 1152, enzastaurin, vandetanib, ARQ-197, MK-0457, MLN8054,PHA-739358, R-763, AT-9263, a FLT-3 inhibitor, a VEGFR inhibitor, anaurora kinase inhibitor, a PIK-1 modulator, an HDAC inhibitor, a c-METinhibitor, a PARP inhibitor, a Cdk inhibitor, an IGFR-TK inhibitor, ananti-HGF antibody, a focal adhesion kinase inhibitor, a Map kinase (mek)inhibitor, a VEGF trap antibody, pemetrexed, panitumumab, amrubicin,oregovomab, Lep-etu, nolatrexed, azd2171, batabulin, ofatumumab,zanolimumab, edotecarin, tetrandrine, rubitecan, tesmilifene,oblimersen, ticilimumab, ipilimumab, gossypol, Bio 111, 131-I-TM-601,ALT-10, BIO 140, CC 8490, cilengitide, gimatecan, IL13-PE38QQR, INO1001, IPdR₁ KRX-0402, lucanthone, LY317615, neuradiab, vitespan, Rta744, Sdx 102, talampanel, atrasentan, Xr 311, romidepsin, ADS-100380,sunitinib, 5-fluorouracil, vorinostat, etoposide, gemcitabine,doxorubicin, liposomal doxorubicin, 5′-deoxy-5-fluorouridine,vincristine, temozolomide, ZK-304709, seliciclib; PD0325901, AZD-6244,capecitabine, L-Glutamic acid,N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-,disodium salt, heptahydrate, camptothecin, PEG-labeled irinotecan,tamoxifen, toremifene citrate, anastrozole, exemestane, letrozole, DES(diethylstilbestrol), estradiol, estrogen, conjugated estrogen,bevacizumab, IMC-1C11, CHIR-258);3-[5-(methylsulfonylpiperadinemethyl)-indolyl-quinolone, vatalanib,AG-013736, AVE-0005, goserelin acetate, leuprolide acetate, triptorelinpamoate, medroxyprogesterone acetate, hydroxyprogesterone caproate,megestrol acetate, raloxifene, bicalutamide, flutamide, nilutamide,megestrol acetate, CP-724714; TAK-165, HKI-272, erlotinib, lapatanib,canertinib, ABX-EGF antibody, erbitux, EKB-569, PKI-166, GW-572016,Ionafamib, BMS-214662, tipifamib; amifostine, NVP-LAQ824, suberoylanalide hydroxamic acid, valproic acid, trichostatin A, FK-228, SU11248,sorafenib, KRN951, aminoglutethimide, amsacrine, anagrelide,L-asparaginase, Bacillus Calmette-Guerin (BCG) vaccine, adriamycin,bleomycin, buserelin, busulfan, carboplatin, carmustine, chlorambucil,cisplatin, cladribine, clodronate, cyproterone, cytarabine, dacarbazine,dactinomycin, daunorubicin, diethylstilbestrol, epirubicin, fludarabine,fludrocortisone, fluoxymesterone, flutamide, gleevec, gemcitabine,hydroxyurea, idarubicin, ifosfamide, imatinib, leuprolide, levamisole,lomustine, mechlorethamine, melphalan, 6-mercaptopurine, mesna,methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, octreotide,oxaliplatin, pamidronate, pentostatin, plicamycin, porfimer,procarbazine, raltitrexed, rituximab, streptozocin, teniposide,testosterone, thalidomide, thioguanine, thiotepa, tretinoin, vindesine,13-cis-retinoic acid, phenylalanine mustard, uracil mustard,estramustine, altretamine, floxuridine, 5-deooxyuridine, cytosinearabinoside, 6-mecaptopurine, deoxycoformycin, calcitriol, valrubicin,mithramycin, vinblastine, vinorelbine, topotecan, razoxin, marimastat,COL-3, neovastat, BMS-275291, squalamine, endostatin, SU5416, SU6668,EMD121974, interleukin-12, IM862, angiostatin, vitaxin, droloxifene,idoxyfene, spironolactone, finasteride, cimitidine, trastuzumab,denileukin diftitox, gefitinib, bortezimib, paclitaxel, cremophor-freepaclitaxel, docetaxel, epithilone B, BMS-247550, BMS-310705,droloxifene, 4-hydroxytamoxifen, pipendoxifene, ERA-923, arzoxifene,fulvestrant, acolbifene, lasofoxifene, idoxifene, TSE-424, HMR-3339,ZK186619, topotecan, PTK787/ZK 222584, VX-745, PD 184352, rapamycin,40-O-(2-hydroxyethyl)-rapamycin, temsirolimus, AP-23573, RAD001,ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646,wortmannin, ZM336372, L-779,450, PEG-filgrastim, darbepoetin,erythropoietin, granulocyte colony-stimulating factor, zolendronate,prednisone, cetuximab, granulocyte macrophage colony-stimulating factor,histrelin, pegylated interferon alfa-2a, interferon alfa-2a, pegylatedinterferon alfa-2b, interferon alfa-2b, azacitidine, PEG-L-asparaginase,lenalidomide, gemtuzumab, hydrocortisone, interleukin-11, dexrazoxane,alemtuzumab, all-transretinoic acid, ketoconazole, interleukin-2,megestrol, immune globulin, nitrogen mustard, methylprednisolone,ibritgumomab tiuxetan, androgens, decitabine, hexamethylmelamine,bexarotene, tositumomab, arsenic trioxide, cortisone, editronate,mitotane, cyclosporine, liposomal daunorubicin, Edwina-asparaginase,strontium 89, casopitant, netupitant, an NK-1 receptor antagonist,palonosetron, aprepitant, diphenhydramine, hydroxyzine, metoclopramide,lorazepam, alprazolam, haloperidol, droperidol, dronabinol,dexamethasone, methylprednisolone, prochlorperazine, granisetron,ondansetron, dolasetron, tropisetron, pegfilgrastim, erythropoietin,epoetin alfa, darbepoetin alfa and mixtures thereof.

In one embodiment, a compound of Formula I, Formula II, Formula III, orFormula IV described herein can be combined with a chemotherapeuticselected from, but are not limited to, Imatinib mesylate (Gleevac®),Dasatinib (Sprycel®), Nilotinib (Tasigna®), Bosutinib (Bosulif®),Trastuzumab (Herceptin®), Pertuzumab (Perjeta™), Lapatinib (Tykerb®),Gefitinib (Iressa®), Erlotinib (Tarceva®), Cetuximab (Erbitux®),Panitumumab (Vectibix®), Vandetanib (Caprelsa®), Vemurafenib(Zelboraf®), Vorinostat (Zolinza®), Romidepsin (Istodax®), Bexarotene(Tagretin®), Alitretinoin (Panretin®), Tretinoin (Vesanoid®),Carfilizomib (Kyprolis™), Pralatrexate (Folotyn®), Bevacizumab(Avastin®), Ziv-aflibercept (Zaltrap®), Sorafenib (Nexavar®), Sunitinib(Sutent®), Pazopanib (Votrient®), Regorafenib (Stivarga®), andCabozantinib (Cometriq™).

In certain aspects, the additional therapeutic agent is ananti-inflammatory agent, a chemotherapeutic agent, a radiotherapeutic,additional therapeutic agents, or immunosuppressive agents.

Suitable chemotherapeutic agents include, but are not limited to,radioactive molecules, toxins, also referred to as cytotoxins orcytotoxic agents, which includes any agent that is detrimental to theviability of cells, agents, and liposomes or other vesicles containingchemotherapeutic compounds. General anticancer pharmaceutical agentsinclude: Vincristine (Oncovin®) or liposomal vincristine (Marqibo®),Daunorubicin (daunomycin or Cerubidine®) or doxorubicin (Adriamycin®),Cytarabine (cytosine arabinoside, ara-C, or Cytosar®), L-asparaginase(Elspar®) or PEG-L-asparaginase (pegaspargase or Oncaspar®), Etoposide(VP-16), Teniposide (Vumon®), 6-mercaptopurine (6-MP or Purinethol®),Methotrexate, Cyclophosphamide (Cytoxan®), Prednisone, Dexamethasone(Decadron), imatinib (Gleevec®), dasatinib (Sprycel®), nilotinib(Tasigna®), bosutinib (Bosulif®), and ponatinib (Iclusig™). Examples ofadditional suitable chemotherapeutic agents include but are not limitedto 1-dehydrotestosterone, 5-fluorouracil decarbazine, 6-mercaptopurine,6-thioguanine, actinomycin D, adriamycin, aldesleukin, alkylatingagents, allopurinol sodium, altretamine, amifostine, anastrozole,anthramycin (AMC)), anti-mitotic agents, cis-dichlorodiamine platinum(II) (DDP) cisplatin), diamino dichloro platinum, anthracycline, anantibiotic, an antimetabolite, asparaginase, BCG live (intravesical),betamethasone sodium phosphate and betamethasone acetate, bicalutamide,bleomycin sulfate, busulfan, calcium leucovorin, calicheamicin,capecitabine, carboplatin, lomustine (CCNU), carmustine (BSNU),Chlorambucil, Cisplatin, Cladribine, Colchicin, conjugated estrogens,Cyclophosphamide, Cyclothosphamide, Cytarabine, Cytarabine, cytochalasinB, Cytoxan, Dacarbazine, Dactinomycin, dactinomycin (formerlyactinomycin), daunirubicin HCL, daunorucbicin citrate, denileukindiftitox, Dexrazoxane, Dibromomannitol, dihydroxy anthracin dione,Docetaxel, dolasetron mesylate, doxorubicin HCL, dronabinol, E. coliL-asparaginase, emetine, epoetin-α, Erwinia L-asparaginase, esterifiedestrogens, estradiol, estramustine phosphate sodium, ethidium bromide,ethinyl estradiol, etidronate, etoposide citrororum factor, etoposidephosphate, filgrastim, floxuridine, fluconazole, fludarabine phosphate,fluorouracil, flutamide, folinic acid, gemcitabine HCL, glucocorticoids,goserelin acetate, gramicidin D, granisetron HCL, hydroxyurea,idarubicin HCL, ifosfamide, interferon α-2b, irinotecan HCL, letrozole,leucovorin calcium, leuprolide acetate, levamisole HCL, lidocaine,lomustine, maytansinoid, mechlorethamine HCL, medroxyprogesteroneacetate, megestrol acetate, melphalan HCL, mercaptipurine, mesna,methotrexate, methyltestosterone, mithramycin, mitomycin C, mitotane,mitoxantrone, nilutamide, octreotide acetate, ondansetron HCL,paclitaxel, pamidronate disodium, pentostatin, pilocarpine HCL,plimycin, polifeprosan 20 with carmustine implant, porfimer sodium,procaine, procarbazine HCL, propranolol, rituximab, sargramostim,streptozotocin, tamoxifen, taxol, teniposide, tenoposide, testolactone,tetracaine, thioepa chlorambucil, thioguanine, thiotepa, topotecan HCL,toremifene citrate, trastuzumab, tretinoin, valrubicin, vinblastinesulfate, vincristine sulfate, and vinorelbine tartrate.

Additional therapeutic agents that can be administered in combinationwith a compound disclosed herein can include bevacizumab, sutinib,sorafenib, 2-methoxyestradiol or 2ME2, finasunate, vatalanib,vandetanib, aflibercept, volociximab, etaracizumab (MEDI-522),cilengitide, erlotinib, cetuximab, panitumumab, gefitinib, trastuzumab,dovitinib, figitumumab, atacicept, rituximab, alemtuzumab, aldesleukine,atlizumab, tocilizumab, temsirolimus, everolimus, lucatumumab,dacetuzumab, HLL1, huN901-DM1, atiprimod, natalizumab, bortezomib,carfilzomib, marizomib, tanespimycin, saquinavir mesylate, ritonavir,nelfinavir mesylate, indinavir sulfate, belinostat, panobinostat,mapatumumab, lexatumumab, dulanermin, ABT-737, oblimersen, plitidepsin,talmapimod, P276-00, enzastaurin, tipifamib, perifosine, imatinib,dasatinib, lenalidomide, thalidomide, simvastatin, celecoxib,bazedoxifene, AZD4547, rilotumumab, oxaliplatin (Eloxatin), PD0332991,ribociclib (LEEO11), amebaciclib (LY2835219), HDM201, fulvestrant(Faslodex), exemestane (Aromasin), PIM447, ruxolitinib (INC424), BGJ398,necitumumab, pemetrexed (Alimta), and ramucirumab (IMC-1121B).

In one aspect of the present invention, a compound described herein canbe combined with at least one immunosuppressive agent. Theimmunosuppressive agent is preferably selected from the group consistingof a calcineurin inhibitor, e.g. a cyclosporin or an ascomycin, e.g.Cyclosporin A (NEORAL®), FK506 (tacrolimus), pimecrolimus, a mTORinhibitor, e.g. rapamycin or a derivative thereof, e.g. Sirolimus(RAPAMUNE®), Everolimus (Certican®), temsirolimus, zotarolimus,biolimus-7, biolimus-9, a rapalog, e.g., ridaforolimus, azathioprine,campath 1H, a S1P receptor modulator, e.g. fingolimod or an analoguethereof, an anti IL-8 antibody, mycophenolic acid or a salt thereof,e.g. sodium salt, or a prodrug thereof, e.g. Mycophenolate Mofetil(CELLCEPT®), OKT3 (ORTHOCLONE OKT3®), Prednisone, ATGAM®,THYMOGLOBULIN®, Brequinar Sodium, OKT4, T10B9.A-3A, 33B3.1,15-deoxyspergualin, tresperimus, Leflunomide ARAVA®, CTLAI-Ig,anti-CD25, anti-IL2R, Basiliximab (SIMULECT®), Daclizumab (ZENAPAX®),mizorbine, methotrexate, dexamethasone, ISAtx-247, SDZ ASM 981(pimecrolimus, Elidel®), CTLA4lg (Abatacept), belatacept, LFA3lg,etanercept (sold as Enbrel® by Immunex), adalimumab (Humira®),infliximab (Remicade®), an anti-LFA-1 antibody, natalizumab (Antegren®),Enlimomab, gavilimomab, antithymocyte immunoglobulin, siplizumab,Alefacept efalizumab, pentasa, mesalazine, asacol, codeine phosphate,benorylate, fenbufen, naprosyn, diclofenac, etodolac and indomethacin,aspirin and ibuprofen.

In certain embodiments, a compound described herein is administered tothe subject prior to treatment with another chemotherapeutic agent,during treatment with another chemotherapeutic agent, afteradministration of another chemotherapeutic agent, or a combinationthereof.

In some embodiments, the compound of Formula I, Formula II, Formula III,or Formula IV can be administered to the subject such that the otherchemotherapeutic agent can be administered either at higher doses(increased chemotherapeutic dose intensity) or more frequently(increased chemotherapeutic dose density). Dose-dense chemotherapy is achemotherapy treatment plan in which drugs are given with less timebetween treatments than in a standard chemotherapy treatment plan.Chemotherapy dose intensity represents unit dose of chemotherapyadministered per unit time. Dose intensity can be increased or decreasedthrough altering dose administered, time interval of administration, orboth.

In one embodiment of the invention, the compounds described herein canbe administered in a concerted regimen with another agent such as anon-DNA-damaging, targeted anti-neoplastic agent or a hematopoieticgrowth factor agent. It has been recently reported that the untimelyadministration of hematopoietic growth factors can have serious sideeffects. For example, the use of the EPO family of growth factors hasbeen associated with arterial hypertension, cerebral convulsions,hypertensive encephalopathy, thromboembolism, iron deficiency, influenzalike syndromes and venous thrombosis. The G-CSF family of growth factorshas been associated with spleen enlargement and rupture, respiratorydistress syndrome, allergic reactions and sickle cell complications. Assuch, in one embodiment, the use of the compounds or methods describedherein is combined with the use of hematopoietic growth factorsincluding, but not limited to, granulocyte colony stimulating factor(G-CSF, for example, sold as Neupogen (filgrastin), Neulasta(peg-filgrastin), or lenograstin), granulocyte-macrophage colonystimulating factor (GM-CSF, for example sold as molgramostim andsargramostim (Leukine)), M-CSF (macrophage colony stimulating factor),thrombopoietin (megakaryocyte growth development factor (MGDF), forexample sold as Romiplostim and Eltrombopag) interleukin (IL)-12,interleukin-3, interleukin-11 (adipogenesis inhibiting factor oroprelvekin), SCF (stem cell factor, steel factor, kit-ligand, or KL) anderythropoietin (EPO), and their derivatives (sold as for exampleepoetin-α as Darbopoetin, Epocept, Nanokine, Epofit, Epogin, Eprex andProcrit; epoetin-β sold as for example NeoRecormon, Recormon andMicera), epoetin-delta (sold as for example Dynepo), epoetin-omega (soldas for example Epomax), epoetin zeta (sold as for example Silapo andReacrit) as well as for example Epocept, EPOTrust, Erypro Safe,Repoeitin, Vintor, Epofit, Erykine, Wepox, Espogen, Relipoeitin,Shanpoietin, Zyrop and EPIAO). In one embodiment, the compound ofFormula I, Formula II, Formula III, or Formula IV is administered priorto administration of the hematopoietic growth factor. In one embodiment,the hematopoietic growth factor administration is timed so that thecompound's effect on HSPCs has dissipated. In one embodiment, the growthfactor is administered at least 20 hours after the administration of acompound described herein.

If desired, multiple doses of a compound described herein can beadministered to the subject. Alternatively, the subject can be given asingle dose of a compound described herein.

In one aspect of the invention, a compound disclosed herein can bebeneficially administered in combination with any therapeutic regimenentailing radiotherapy, chemotherapy, or other therapeutic agents. Inadditional embodiments the compounds disclosed herein can bebeneficially administered in combination with therapeutic agentstargeting auto-immune disorders.

VIII. Synthesis

The compounds described herein can be prepared by methods known by thoseskilled in the art. In one non-limiting example, the disclosed compoundscan be made by the following schemes.

The disclosed compounds can be made by the following general schemes:

As demonstrated in Scheme 1, thiolactam compounds that adhere to FormulaI can be prepared from readily available pyrimidines. In Step 1, anappropriately substituted pyrimidine is reacted with an appropriatelysubstituted amine to afford selective displacement of chloride. In Step2, the appropriately substituted pyrimidine is coupled to a terminalalkyne to afford a cyclization precursor. In Step 3, the cyclizationprecursor is cyclized in the presence of TBAF to afford a bicyclicheteroaryl compound. In Step 4, the bicyclic heteroaryl compound isdeprotected as known in the art to afford an aldehyde. In Step 5, thealdehyde is oxidized as known in the art to afford a carboxylic acid. InStep 6, the carboxylic acid is alkylated to afford an ester. In Step 7,the carbamate is removed by strong acid. In Step 8, the moleculeundergoes intramolecular cyclization to afford Intermediate 1. In Step9, Intermediate 1 is then subjected to Lawesson's Reagent at reflux toafford Intermediate 2. In Step 10, the last halogen of Intermediate 2 isdisplaced by a heteroaryl amine to afford a compound of Formula I.

As demonstrated in Scheme 2, thiolactam compounds that adhere to FormulaI can be prepared from readily available pyrimidines. In Step 1, anappropriately substituted pyrimidine is reacted with an appropriatelysubstituted amine to afford selective displacement of chloride. In Step2, the appropriately substituted pyrimidine is coupled to a terminalalkyne to afford a cyclization precursor. In Step 3, the cyclizationprecursor is cyclized in the presence of TBAF to afford a bicyclicheteroaryl compound. In Step 4, the bicyclic heteroaryl compound isdeprotected as known in the art to afford an aldehyde. In Step 5, thealdehyde is oxidized as known in the art to afford a carboxylic acid. InStep 6, the carboxylic acid is alkylated to afford an ester. In Step 7,the carbamate is removed by strong acid. In Step 8, the moleculeundergoes intramolecular cyclization to afford Intermediate 3. In Step9, Intermediate 3 is then subjected to Lawesson's Reagent at reflux toafford Intermediate 4. In Step 10, the last halogen of Intermediate 4 isdisplaced by a heteroaryl amine to afford a compound of Formula I.

As demonstrated in Scheme 3, compounds that adhere to Formula I can beprepared from Intermediates from Scheme 1 and Scheme 2. In Step 1,Intermediate 1 or Intermediate 3 is reacted with an amine to afforddehydration. In Step 2, the appropriately substituted halo pyrimidine isdisplaced by a heteroaryl amine to afford a compound of Formula I.

As demonstrated in Scheme 4, compounds that adhere to Formula II can beprepared from commercially available pyrimidines. In Step 1, anappropriately substituted pyrimidine is reacted with an appropriatelysubstituted amine to afford selective displacement of chloride. In Step2, the appropriately substituted pyrimidine is coupled to a terminalalkyne to afford a cyclization precursor. In Step 3, the cyclizationprecursor is cyclized in the presence of TBAF to afford a bicyclicheteroaryl compound. In Step 4, the bicyclic heteroaryl compound isdeprotected as known in the art to afford an aldehyde. In Step 5, thecarbamate is removed by strong acid affording an intramolecularcyclization. In Step 6, the imine is reduced as known in the art toafford an amine. In Step 7, the last halogen of is displaced by aheteroaryl amine to afford a compound of Formula II.

As demonstrated in Scheme 5, compounds that adhere to Formula III can beprepared from Intermediate 2. In Step 1, Intermediate 2 is reacted withan amine to afford nucleophilic displacement. In Step 2, theappropriately substituted halo pyrimidine is displaced by a heteroarylamine to afford a compound of Formula III.

Alternatively, as described in Scheme 6, compounds that adhere toFormula III can be prepared from Intermediate 2. In Step 1, Intermediate2 is reacted with an alkyl iodide under oxidative conditions to afford asulfonyl compound. In Step 2, the sulfonyl compound is reacted with anamine to afford nucleophilic displacement. In Step 3, the appropriatelysubstituted halo pyrimidine is displaced by a heteroaryl amine to afforda compound of Formula III.

As demonstrated in Scheme 7, sulfonamide compounds that adhere toFormula IV can be prepared from readily available pyrimidines. In Step1, an appropriately substituted indole is reacted with an appropriatelysubstituted alkyl chloride to afford a substituted indole. In Step 2,the pyrimidine halogen is displaced by a heteroaryl amine to afford ananiline. In Step 3, the aniline is protected with a protecting group,PG, known to those skilled in the arts. In Step 4, the indole is reactedwith n-BuLi and SO₂ gas to afford a sulfone. In Step 5, the protectedamine is deprotected as known in the art to afford the cyclic precursorthat in Step 6 undergoes cyclization in the presence of a weak base. InStep 7, the aniline is deprotected as known to those skilled in the artto afford a compound of Formula VI

Representative synthetic Schemes of the above general synthetic Schemesis provided below.

IX. Exemplary Compounds

X. Examples

General Methods:

¹H NMR spectra were recorded on a 300 MHz Fourier transform Brückerspectrometer. Spectra were obtained from samples prepared in 5 mmdiameter tubes in CDCl₃, CD₃OD or DMSO-d₆. The spin multiplicities areindicated by the symbols s (singlet), d (doublet), t (triplet), m(multiplet) and, br (broad). Coupling constants (J) are reported in Hz.MS spectra were obtained using electrospray ionization (ESI) on anAgilent Technologies 6120 quadrupole MS apparatus. The reactions weregenerally carried out under a dry nitrogen atmosphere usingSigma-Aldrich anhydrous solvents. All common chemicals were purchasedfrom commercial sources.

Compounds of the present invention with stereocenters are drawn racemicfor convenience. One skilled in the art will recognize that pureenantiomers can be prepared by methods known in the art. Examples ofmethods to obtain optically active materials include at least thefollowing.

i) physical separation of crystals—a technique whereby macroscopiccrystals of the individual enantiomers are manually separated. Thistechnique can be used if crystals of the separate enantiomers exist,i.e., the material is a conglomerate, and the crystals are visuallydistinct;

ii) simultaneous crystallization—a technique whereby the individualenantiomers are separately crystallized from a solution of the racemate,possible only if the latter is a conglomerate in the solid state;

iii) enzymatic resolutions—a technique whereby partial or completeseparation of a racemate by virtue of differing rates of reaction forthe enantiomers with an enzyme;

iv) enzymatic asymmetric synthesis—a synthetic technique whereby atleast one step of the synthesis uses an enzymatic reaction to obtain anenantiomerically pure or enriched synthetic precursor of the desiredenantiomer;

v) chemical asymmetric synthesis—a synthetic technique whereby thedesired enantiomer is synthesized from an achiral precursor underconditions that produce asymmetry (i.e., chirality) in the product,which may be achieved using chiral catalysts or chiral auxiliaries;

vi) diastereomer separations—a technique whereby a racemic compound isreacted with an enantiomerically pure reagent (the chiral auxiliary)that converts the individual enantiomers to diastereomers. The resultingdiastereomers are then separated by chromatography or crystallization byvirtue of their now more distinct structural differences and the chiralauxiliary later removed to obtain the desired enantiomer;

vii) first- and second-order asymmetric transformations—a techniquewhereby diastereomers from the racemate equilibrate to yield apreponderance in solution of the diastereomer from the desiredenantiomer or where preferential crystallization of the diastereomerfrom the desired enantiomer perturbs the equilibrium such thateventually in principle all the material is converted to the crystallinediastereomer from the desired enantiomer. The desired enantiomer is thenreleased from the diastereomer;

viii) kinetic resolutions—this technique refers to the achievement ofpartial or complete resolution of a racemate (or of a further resolutionof a partially resolved compound) by virtue of unequal reaction rates ofthe enantiomers with a chiral, non-racemic reagent or catalyst underkinetic conditions;

ix) enantiospecific synthesis from non-racemic precursors—a synthetictechnique whereby the desired enantiomer is obtained from non-chiralstarting materials and where the stereochemical integrity is not or isonly minimally compromised over the course of the synthesis;

x) chiral liquid chromatography—a technique whereby the enantiomers of aracemate are separated in a liquid mobile phase by virtue of theirdiffering interactions with a stationary phase (including via chiralHPLC). The stationary phase can be made of chiral material or the mobilephase can contain an additional chiral material to provoke the differinginteractions;

xi) chiral gas chromatography—a technique whereby the racemate isvolatilized and enantiomers are separated by virtue of their differinginteractions in the gaseous mobile phase with a column containing afixed non-racemic chiral adsorbent phase;

xii) extraction with chiral solvents—a technique whereby the enantiomersare separated by virtue of preferential dissolution of one enantiomerinto a particular chiral solvent;

xiii) transport across chiral membranes—a technique whereby a racemateis placed in contact with a thin membrane barrier. The barrier typicallyseparates two miscible fluids, one containing the racemate, and adriving force such as concentration or pressure differential causespreferential transport across the membrane barrier. Separation occurs asa result of the non-racemic chiral nature of the membrane that allowsonly one enantiomer of the racemate to pass through.

Chiral chromatography, including simulated moving bed chromatography, isused in one embodiment. A wide variety of chiral stationary phases arecommercially available.

Example 1. Preparation of Substituted 2-Aminopyridines1-Methyl-4-(6-nitro-3-pyridyl)piperazine

To 5-bromo-2-nitropyridine (4.93 g, 24.3 mmole) in DMF (20 mL) was addedN-methylpiperazine (2.96 g, 1.1 eq) followed by the addition of DIPEA(4.65 mL, 26.7 mmole). The contents were heated at 90° C. for 24 hrs.After the addition of ethyl acetate (200 mL), water (100 mL) was addedand the layers were separated. Drying followed by concentration affordedthe crude product which was purified on a silica gel column using(0-10%) DCM/Methanol.

¹H NMR (DMSO-d₆) δ 8.26 (s, 1H), 8.15 (1H, d, J=9.3 Hz), 7.49 (1H, d,J=9.4 Hz), 3.50 (m, 4H), 2.49 (m, 4H), 2.22 (s, 3H).

5-(4-Methylpiperazin-1-yl)pyridin-2-amine

To 1-methyl-4-(6-nitro-3-pyridyl)piperazine 3.4 g in ethyl acetate (100mL) and ethanol (100 mL) was added 10% Pd/c (400 mg) and then contentsstirred under hydrogen (10 psi) overnight. After filtration throughCelite®, the solvents were evaporated and the crude product was purifiedover silica gel using DCM/7N Ammonia in MeOH (0-5%) to afford5-(4-methylpiperazin-1-yl)pyridin-2-amine (2.2 g).

¹HNMR (DMSO-d₆) δ 7.56 (1H, d, J=3 Hz), 7.13 (1H, m), 6.36 (1H, d, J=8.8Hz), 5.33 (brs, 2H), 2.88 (m, 4H), 2.47 (m, 4H), 2.16 (s, 3H).

tert-Butyl 4-(6-amino-3-pyridyl)piperazine-1-carboxylate

The compound was prepared as described in WO 2010/020675 A1.

To 5-bromo-2-nitropyridine (1.2 g, 5.9 mmole) in DMSO (4 mL) was added1-(4-piperidyl)piperidine (1.0 g, 5.9 mmole) and triethylamine (0.99 mL,7.1 mmole). The contents were heated to 120° C. in a CEM Discoverymicrowave system for 3 hours. The crude reaction was then loaded over asilica gel column and eluted with DCM/methanol (0-20%) to afford2-nitro-5-[4-(1-piperidyl)-1-piperidyl]pyridine as an oil (457 mg).

¹H NMR (600 MHz, DMSO-d₆) δ ppm 1.26-1.36 (m, 2H) 1.43 (m, 6H) 1.76 (m,2H) 2.37 (m, 5H) 2.94 (t, J=12.74 Hz, 2H) 4.06 (d, J=13.47 Hz, 2H) 7.41(dd, J=9.37, 2.64 Hz, 1H) 8.08 (d, J=9.37 Hz, 1H) 8.20 (d, J=2.64 Hz,1H).

5-[4-(1-Piperidyl)-1-piperidyl]pyridin-2-amine

5-[4-(1-Piperidyl)-1-piperidyl]pyridin-2-amine was prepared in a mannersimilar to that used in the synthesis of5-(4-methylpiperazin-1-yl)pyridin-2-amine.

¹H NMR (600 MHz, DMSO-d₆) δ ppm 1.13-1.37 (m, 6H) 1.40-1.63 (m, 6H) 1.71(m, 2H), 2.24 (m, 1H) 2.43 (m, 2H) 3.33 (d, J=12.30 Hz, 2H) 5.31 (s, 2H)6.33 (d, J=8.78 Hz, 1H) 7.10 (dd, J=8.78, 2.93 Hz, 1H) 7.55 (d, J=2.64Hz, 1H). LCMS (ESI) 261 (M+H).

4-[1-(6-Nitro-3-pyridyl)-4-piperidyl] morpholine

4-[1-(6-Nitro-3-pyridyl)-4-piperidyl]morpholine was synthesized in amanner similar to that used in the synthesis of2-nitro-5-[4-(1-piperidyl)-1-piperidyl]pyridine.

1H NMR (600 MHz, DMSO-d₆) δ ppm 1.41 (m, 2H) 1.82 (m, 2H) 2.42 (m, 5H)2.98 (t, J=12.44 Hz, 2H) 3.52 (s, 4H) 4.04 (d, J=12.88 Hz, 2H) 7.42 (d,J=9.37 Hz, 1H) 8.08 (d, J=9.08 Hz, 1H) 8.21 (s, 1H).

5-(4-Morpholino-1-piperidyl) pyridin-2-amine

5-(4-Morpholino-1-piperidyl)pyridin-2-amine was prepared in a mannersimilar to that used in the synthesis of5-(4-methylpiperazin-1-yl)pyridin-2-amine.

¹H NMR (600 MHz, DMSO-d₆) δ ppm 1.34-1.52 (m, 2H) 1.78 (m, 2H) 2.14 (m,1H) 2.43 (m, 4H) 3.32 (d, J=12.30 Hz, 4H) 3.47-3.59 (m, 4H) 5.32 (s, 2H)6.34 (d, J=8.78 Hz, 1H) 7.11 (dd, J=8.93, 2.78 Hz, 1H) 7.47-7.62 (m,1H). LCMS (ESI) 263 (M+H).

4-[1-(6-Nitro-3-pyridyl)-4-piperidyl] thiomorpholine

4-[1-(6-Nitro-3-pyridyl)-4-piperidyl] thiomorpholine was synthesized ina manner similar to that used in the synthesis of2-nitro-5-[4-(1-piperidyl)-1-piperidyl]pyridine.

¹H NMR (600 MHz, DMSO-d₆) δ ppm 1.40-1.52 (m, 2H) 1.71 (m, 2H) 2.49-2.55(m, 4H) 2.56-2.63 (m, 1H) 2.68-2.75 (m, 4H) 2.88-2.98 (m, 2H) 4.09 (d,J=13.18 Hz, 2H) 7.42 (dd, J=9.22, 3.07 Hz, 1H) 8.08 (d, J=9.37 Hz, 1H)8.20 (d, J=3.22 Hz, 1H).

5-(4-Thiomorpholino-1-piperidyl) pyridin-2-amine

5-(4-Thiomorpholino-1-piperidyl) pyridin-2-amine was prepared in amanner similar to that used in the synthesis of5-(4-methylpiperazin-1-yl)pyridin-2-amine.

¹H NMR (600 MHz, DMSO-d₆) δ ppm 1.47-1.59 (m, 2H) 1.65 (m, 2H) 2.22-2.38(m, 1H) 2.50-2.59 (m, 6H) 2.68-2.82 (m, 4H) 3.33 (d, J=12.00 Hz, 2H)5.31 (s, 2H) 6.33 (d, J=9.08 Hz, 1H) 7.10 (dd, J=8.78, 2.93 Hz, 1H) 7.55(d, J=2.64 Hz, 1H). LCMS (ESI) 279 (M+H).

2-Nitro-5-(1-piperidyl)pyridine

2-Nitro-5-(1-piperidyl) pyridine was synthesized in a manner similar tothat used in the synthesis of2-nitro-5-[4-(1-piperidyl)-1-piperidyl]pyridine.

¹H NMR (600 MHz, DMSO-d₆) δ ppm 1.56 (m, 6H) 3.49 (d, J=4.39 Hz, 4H)7.30-7.47 (m, 1H) 8.02-8.12 (m, 1H) 8.15-8.26 (m, 1H).

5-(1-Piperidyl)pyridin-2-amine

5-(1-Piperidyl) pyridin-2-amine was prepared in a manner similar to thatused in the synthesis of 5-(4-methylpiperazin-1-yl)pyridin-2-amine.

¹H NMR (600 MHz, DMSO-d₆) δ ppm 1.39-1.46 (m, 2H) 1.51-1.62 (m, 4H)2.75-2.92 (m, 4H) 5.30 (s, 2H) 6.34 (d, J=8.78 Hz, 1H) 7.09 (dd, J=8.78,2.93 Hz, 1H) 7.54 (d, J=2.93 Hz, 1H). LCMS (ESI) 178 (M+H).

4-(6-Nitro-3-pyridyl) thiomorpholine

4-(6-nitro-3-pyridyl) thiomorpholine was synthesized in a manner similarto that used in the synthesis of2-nitro-5-[4-(1-piperidyl)-1-piperidyl]pyridine.

¹H NMR (600 MHz, DMSO-d₆) δ ppm 2.56-2.69 (m, 4H) 3.79-3.92 (m, 4H) 7.43(dd, J=9.22, 3.07 Hz, 1H) 8.10 (d, J=9.37 Hz, 1H) 8.20 (d, J=2.93 Hz,1H).

5-Thiomorpholinopyridin-2-amine

5-Thiomorpholinopyridin-2-amine was prepared in a manner similar to thatused in the synthesis of 5-(4-methylpiperazin-1-yl) pyridin-2-amine.

¹H NMR (600 MHz, DMSO-d₆) δ ppm 2.59-2.73 (m, 4H) 3.04-3.20 (m, 4H) 5.41(s, 2H) 6.35 (d, J=8.78 Hz, 1H) 7.10 (dd, J=8.78, 2.93 Hz, 1H) 7.57 (d,J=2.64 Hz, 1H). LCMS (ESI) 196 (M+H).

tert-Butyl(4R)-5-(6-nitro-3-pyridyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

tert-Butyl(4R)-5-(6-nitro-3-pyridyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylatewas synthesized in a manner similar to that used in the synthesis of2-nitro-5-[4-(1-piperidyl)-1-piperidyl]pyridine.

¹H NMR (600 MHz, DMSO-d₆) δ ppm 1.33 (d, J=32.21 Hz, 11H) 1.91 (m, 2H)3.15 (d, J=10.25 Hz, 1H) 3.58 (m, 1H) 4.46 (m, 1H) 4.83 (s, 1H) 7.16 (s,1H) 7.94 (s, 1H) 8.05-8.16 (m, 1H).

tert-Butyl(4R)-5-(6-amino-3-pyridyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

tert-Butyl(4R)-5-(6-amino-3-pyridyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylatewas prepared in a manner similar to that used in the synthesis of5-(4-methylpiperazin-1-yl)pyridin-2-amine.

¹H NMR (600 MHz, DMSO-d₆) δ ppm 1.31 (d, J=31.91 Hz, 11H) 1.83 (m, 2H)2.71-2.82 (m, 1H) 3.44 (m, 1H) 4.30 (d, 2H) 5.08 (s, 2H) 6.35 (d, J=8.78Hz, 1H) 6.77-6.91 (m, 1H) 7.33 (s, 1H). LCMS (ESI) 291 (M+H).

N,N-dimethyl-1-(6-nitro-3-pyridyl) piperidin-4-amine

N,N-dimethyl-1-(6-nitro-3-pyridyl)piperidin-4-amine was synthesized in amanner similar to that used in the synthesis of2-nitro-5-[4-(1-piperidyl)-1-piperidyl]pyridine.

¹H NMR (600 MHz, DMSO-d₆) δ ppm 1.30-1.45 (m, 2H) 1.79 (m, 2H) 2.14 (s,6H) 2.33 (m, 1H) 2.92-3.04 (m, 2H) 4.03 (d, J=13.76 Hz, 2H) 7.42 (dd,J=9.22, 3.07 Hz, 1H) 8.04-8.11 (m, 1H) 8.21 (d, J=2.93 Hz, 1H).

5-[4-(Dimethylamino)-1-piperidyl] pyridin-2-amine

5-[4-(dimethylamino)-1-piperidyl]pyridin-2-amine was prepared in amanner similar to that used in the synthesis of5-(4-methylpiperazin-1-yl)pyridin-2-amine.

¹H NMR (600 MHz, DMSO-d₆) δ ppm 1.35-1.50 (m, 2H) 1.69-1.81 (m, 2H)2.00-2.10 (m, 1H) 2.11-2.22 (s, 6H) 3.17-3.36 (m, 4H) 5.19-5.38 (s, 2H)6.34 (d, J=8.78 Hz, 1H) 7.10 (dd, J=8.78, 2.93 Hz, 1H) 7.55 (d, J=2.63Hz, 1H). LCMS (ESI) 221 (M+H).

4-(6-Nitro-3-pyridyl) morpholine

4-(6-Nitro-3-pyridyl) morpholine was synthesized in a manner similar tothat used in the synthesis of 2-nitro-5-[4-(1-piperidyl)-1-piperidyl]pyridine.

5-Morpholinopyridin-2-amine

5-Morpholinopyridin-2-amine was prepared in a manner similar to thatused in the synthesis of 5-(4-methylpiperazin-1-yl) pyridin-2-amine.

¹H NMR (600 MHz, CHCl₃-d) δ ppm 2.91-3.00 (m, 4H) 3.76-3.84 (m, 4H) 4.19(br. s., 2H) 6.45 (d, J=8.78 Hz, 1H) 7.12 (dd, J=8.78, 2.93 Hz, 1H) 7.72(d, J=2.93 Hz, 1H).

5-(4-Isobutylpiperazin-1-yl) pyridin-2-amine

1-Isobutyl-4-(6-nitro-3-pyridyl)piperazine was synthesized in a mannersimilar to that used in the synthesis of2-nitro-5-[4-(1-piperidyl)-1-piperidyl]pyridine which was then converted5-(4-isobutylpiperazin-1-yl)pyridin-2-amine in a manner similar to thatused in the synthesis of 5-(4-methylpiperazin-1-yl)pyridin-2-amine.

¹H NMR (600 MHz, CHCl₃-d) δ ppm 0.88 (d, J=6.73 Hz, 6H) 1.71-1.84 (m,1H) 2.10 (d, J=7.32 Hz, 2H) 2.46-2.58 (m, 4H) 2.97-3.07 (m, 4H) 4.12 (s,2H) 6.45 (d, J=8.78 Hz, 1H) 7.14 (dd, J=8.78, 2.93 Hz, 1H) 7.75 (d,J=2.93 Hz, 1H). LCMS (ESI) 235 (M+H).

5-(4-Isopropylpiperazin-1-yl) pyridin-2-amine

1-Isopropyl-4-(6-nitro-3-pyridyl)piperazine was synthesized in a mannersimilar to that used in the synthesis of2-nitro-5-[4-(1-piperidyl)-1-piperidyl]pyridine which was then convertedto 5-(4-isopropylpiperazin-1-yl)pyridin-2-amine in a manner similar tothat used in the synthesis of 5-(4-methylpiperazin-1-yl)pyridin-2-amine.

¹H NMR (600 MHz, CHCl₃-d) δ ppm 1.06 (d, J=6.44 Hz, 6H) 2.59-2.75 (m,5H) 2.97-3.10 (m, 4H) 4.13 (s, 2H) 6.45 (d, J=8.78 Hz, 1H) 7.15 (dd,J=9.08, 2.93 Hz, 1H) 7.76 (d, J=2.93 Hz, 1H). LCMS (ESI) 221 (M+H).

5-[(2R,6S)-2,6-Dimethylmorpholin-4-yl]pyridin-2-amine

(2S,6R)-2,6-Dimethyl-4-(6-nitro-3-pyridyl)morpholine was synthesized ina manner similar to that used in the synthesis of2-nitro-5-[4-(1-piperidyl)-1-piperidyl]pyridine which was then convertedto 5-[(2R,6S)-2,6-dimethylmorpholin-4-yl]pyridin-2-amine in a mannersimilar to that used in the synthesis of5-(4-methylpiperazin-1-yl)pyridin-2-amine. ¹H NMR (600 MHz, CHCl₃-d) δppm 1.20 (d, J=6.44 Hz, 6H) 2.27-2.39 (m, 2H) 3.11-3.21 (m, 2H)3.70-3.84 (m, 2H) 4.15 (s, 2H) 6.45 (d, J=8.78 Hz, 1H) 7.12 (dd, J=8.78,2.93 Hz, 1H) 7.72 (d, J=2.63 Hz, 1H). LCMS (ESI) 208 (M+H).

5-[(3R,5S)-3,5-Dimethylpiperazin-1-yl]pyridin-2-amine

(3S,5R)-3,5-Dimethyl-1-(6-nitro-3-pyridyl)piperazine was synthesized ina manner similar to that used in the synthesis of2-nitro-5-[4-(1-piperidyl)-1-piperidyl]pyridine which was then convertedto 5-[(3R,5S)-3,5-dimethylpiperazin-1-yl]pyridin-2-amine in a mannersimilar to that used in the synthesis of5-(4-methylpiperazin-1-yl)pyridin-2-amine. ¹H NMR (600 MHz, CHCl₃-d) δppm 1.09 (d, J=6.44 Hz, 6H) 2.20 (t, J=10.83 Hz, 2H) 2.95-3.08 (m, 2H)3.23 (dd, J=11.71, 2.05 Hz, 2H) 4.13 (s, 2H) 6.45 (d, J=8.78 Hz, 1H)7.14 (dd, J=8.78, 2.93 Hz, 1H) 7.73 (d, J=2.63 Hz, 1H). LCMS (ESI) 207(M+H).

Example 2: Preparation of Final Compounds

Step 1: Synthesis of tert-Butyl ((1-((2-chloro-5-iodopyrimidin-4-yl)amino)cyclohexyl)methyl)carbamate (3)

To a solution of 2,4-dichloro-5-iodopyrimidine (1, 25 g, 91.2 mmol) andtert-butyl ((1-aminocyclohexyl)methyl)carbamate (2, 20.5 g, 89.9 mmol)in DMF (100 mL) was added K₂CO₃ (12.4 g, 89.2 mmol). The reactionmixture was stirred at 80° C. for 12 h. After cooling to roomtemperature, the reaction mixture was quenched with water (200 mL) andextracted with EtOAc (200 mL). The organic layer was separated andwashed with brine, dried over MgSO₄, filtered and concentrated in vacuo.The resulting crude product was purified by column chromatography toprovide tert-butyl((1-((2-chloro-5-iodopyrimidin-4-yl)amino)cyclohexyl)methyl)carbamate(3, 28 g, 60.1 mmol). MS (ESI+): m/z 467 [M+H]⁺.

Step 2: Synthesis of tert-Butyl((1-((2-chloro-5-(3,3-diethoxyprop-1-yn-1-yl)pyrimidin-4-yl)amino)cyclohexyl)methyl)carbamate(5)

Under N₂ atmosphere, to a solution of tert-butyl((1-((2-chloro-5-iodopyrimidin-4-yl)amino)cyclohexyl)methyl)carbamate(3, 6 g, 12.9 mmol) and DIEA (3.9 mL, 22.4 mmol) in anhydrous THF (150mL) was added CuI (120 mg, 0.6 mmol) and PdCl₂(PPh₃)₂ (167 mg, 0.2mmol). 3,3-diethoxyprop-1-yne (4, 2.81 g, 21.9 mmol) was then addeddropwise. After stirring at room temperature for 4 h, the reactionmixture was quenched with water (200 mL) and extracted with EtOAc (200mL). The organic layer was separated and washed with brine, dried overMgSO₄, filtered and concentrated in vacuo. The resulting crude productwas purified by column chromatography to provide tert-butyl((1-((2-chloro-5-(3,3-diethoxyprop-1-yn-1-yl)pyrimidin-4-yl)amino)cyclohexyl)methyl)carbamate(5, 3.5 g, 7.5 mmol). MS (ESI+): m/z 467 [M+H]⁺.

Step 3: Synthesis of tert-Butyl((1-(2-chloro-6-(diethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexyl)methyl)carbamate (6)

To a solution of tert-butyl((1-((2-chloro-5-(3,3-diethoxyprop-1-yn-1-yl)pyrimidin-4-yl)amino)cyclohexyl)methyl)carbamate(5, 3.4 g, 7.3 mmol) in anhydrous THF (150 mL) was added TBAF (6.8 g,21.6 mmol). The reaction was stirred at 60° C. for 4 h. After cooling toroom temperature, the reaction mixture was quenched with water (150 mL)and extracted with EtOAc (150 mL). The organic layer was separated andwashed with brine, dried over MgSO4, filtered and concentrated in vacuo.The crude product was purified by column chromatography to affordtert-butyl((1-(2-chloro-6-(diethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexyl)methyl)carbamate(6, 1.6 g, 3.4 mmol).

Step 4: Synthesis of tert-Butyl((1-(2-chloro-6-formyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexyl)methyl)carbamate(7)

To a solution of tert-butyl((1-(2-chloro-6-(diethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexyl)methyl)carbamate(6, 1.6 g, 3.4 mmol) in THF (3 mL) was added HOAc (3 mL) and water (3mL). After stirring at 60° C. overnight, the reaction mixture wasneutralized with saturated aqueous NaHCO₃ and extracted with EtOAc (20mL×2). The combined organic phases were washed with brine, dried overMgSO₄, filtered and concentrated in vacuo. The resulting crude productwas purified by column chromatography to provide tert-butyl((1-(2-chloro-6-formyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexyl)methyl)carbamate(7, 1.0 g, 2.5 mmol). MS (ESI+): m/z 393 [M+H]⁺.

Step 5: Synthesis of2′-Chloro-8′H-spiro[cyclohexane-1,9′-pyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyrimidine](8)

To a solution of tert-butyl((1-(2-chloro-6-formyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexyl)methyl)carbamate(7, 200 mg, 0.51 mmol) in DCM (10 mL) was added TFA (3 mL). Afterstirring at room temperature for 1 h, the reaction mixture wasneutralized with aqueous sodium bicarbonate solution and extracted withDCM (10 mL×3). The combined organic phases were washed with brine, driedover MgSO₄, filtered and concentrated in vacuo. The resulting crudeproduct was purified by column chromatography to afford2′-chloro-8′H-spiro[cyclohexane-1,9′-pyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyrimidine] (8, 180 mg, 0.65 mmol). MS (ESI+): m/z 275[M+H]⁺.

Step 6: Synthesis ofN-(5-(4-Methylpiperazin-1-yl)pyridin-2-yl)-8′H-spiro[cyclohexane-1,9′-pyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyrimidin]-2′-amine(Compound 1)

Under N₂ atmosphere, to a solution of2′-chloro-8′H-spiro[cyclohexane-1,9′-pyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyrimidine](8, 122 mg, 0.08 mmol) 5-(4-methylpiperazin-1-yl)pyridin-2-amine (15.3mg, 0.08 mmol), Pd₂(dba)₃ (7.32 mg, 0.008 mmol) and BINAP (9.96 mg,0.016 mmol) in toluene (4 mL) was added LHMDS (0.12 mL, 1 M in THF).After stirring at 100° C. for 3 h, the reaction mixture was cooled toroom temperature, quenched with water (10 mL) and extracted with EtOAc(10 mL). The organic layer was separated and concentrated in vacuo. Theresulting residue was purified by prep TLC to provideN-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)-8′H-spiro[cyclohexane-1,9′-pyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyrimidin]-2′-amine (COMPOUND 1, 3 mg, 0.007 mmol). MS(ESI+): m/z 431 [M+H]⁺; ¹H NMR (300 MHz, CDCl₃): δ 8.74 (s, 1H), 8.36(s, 1H), 8.28 (d, J=9.0 Hz, 1H), 8.02 (d, J=2.7 Hz, 1H), 7.88 (s, 1H),7.31 (dd, J=9.0, 3.0 Hz, 1H), 6.61 (s, 1H), 4.07 (s, 2H), 3.19 (t,J=10.4 Hz, 4H), 2.90 (td, J=13.2, 4.2 Hz, 2H), 2.62 (t, J=4.8 Hz, 4H),2.38 (s, 3H), 2.38 (s, 3H), 2.04-1.80 (m, 5H), 1.58-1.41 (m, 3H).

To a solution ofN-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)-8′H-spiro[cyclohexane-1,9′-pyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyrimidin]-2′-amine(COMPOUND 1, 100 mg, 0.23 mmol) in MeOH (5 mL) was added Pd/C (30 mg,0.03 mmol). The reaction was degassed and backfilled with hydrogen threetimes. After stirring under hydrogen atmosphere for 12 h, the reactionmixture was filtered and concentrated in vacuo. The resulting residuewas purified by prep TLC to provideN-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)-7′,8′-dihydro-6′H-spiro[cyclohexane-1,9′-pyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyrimidin]-2′-amine (COMPOUND 2, 5.9 mg, 0.014 mmol).MS (ESI+): m/z 433 [M+H]⁺; ¹H NMR (300 MHz, MeOD): δ8.52 (s, 1H), 7.96(br s, 1H), 7.87 (d, J=2.4 Hz, 1H), 7.52 (s, 1H), 6.18 (s, 1H),4.36-4.16 (m, 2H), 4.08 (s, 2H), 3.34-3.25 (m, 4H), 3.15-3.08 (m, 2H),3.08-3.00 (m, 4H), 2.61 (s, 3H), 1.79-1.74 (m, 5H), 1.51-1.44 (m, 3H).

Step 1: Synthesis of tert-Butyl2′-chloro-6′-oxo-6′H-spiro[cyclohexane-1,9′-pyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyrimidine]-7′(8′H)-carboxylate(10)

To a solution of tert-butyl((1-(2-chloro-6-formyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexyl)methyl)carbamate(9, 200 mg, 0.51 mmol), NaH₂PO₄ (636 mg, 4.08 mmol) and2-methylbut-2-ene (286 mg, 4.08 mmol) in t-BuOH (25 mL) and acetonitrile(5 mL) at 0° C. was added a solution of NaClO₂ (369 mg, 4.08 mmol) inwater (10 mL) in dropwise. After stirring at room temperature for 2 h,the reaction mixture was extracted with EtOAc (10 mL×2). The combinedorganic phases were washed with brine, dried over MgSO₄, filtered andconcentrated in vacuo. The resulting crude product was purified bycolumn chromatography to provide tert-butyl2′-chloro-6′-oxo-6′H-spiro[cyclohexane-1,9′-pyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyrimidine]-7′(8′H)-carboxylate (10, 180 mg, 0.46mmol). MS (ESI+): m/z 391 [M+H]⁺.

Step 2: Synthesis of2′-Chloro-7′,8′-dihydro-6′H-spiro[cyclohexane-1,9′-pyrazino [1′,2′:1,5]pyrrolo[2,3-d]pyrimidin]-6′-one (11)

To a solution of tert-butyl2′-chloro-6′-oxo-6′H-spiro[cyclohexane-1,9′-pyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyrimidine]-7′(8′H)-carboxylate (10, 160 mg, 0.41mmol) in DCM (10 mL) was added TFA (0.3 mL). After stirring at roomtemperature for 3 h, the reaction mixture was neutralized with aqueoussodium bicarbonate solution and extracted with EtOAc (20 mL×2). Thecombined organic phases were washed with brine, dried over MgSO₄,filtered and concentrated in vacuo. The resulting crude product waspurified by column chromatography to provide2′-chloro-7′,8′-dihydro-6′H-spiro[cyclohexane-1,9′-pyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyrimidin]-6′-one(11, 80 mg, 0.27 mmol). MS (ESI+): m/z 291 [M+H]⁺.

Step 3: Synthesis of2′-Chloro-7′,8′-dihydro-6′H-spiro[cyclohexane-1,9′-pyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyrimidine]-6′-thione(12)

To a solution of2′-chloro-7′,8′-dihydro-6′H-spiro[cyclohexane-1,9′-pyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyrimidin]-6′-one(11, 0.8 g, 2.75 mmol) in THF (20 mL) was added Lawesson reagent (1.4 g,3.46 mmol). After stirring under reflux for 2 h, the reaction mixturewas concentrated in vacuo. The resulting residue was purified by columnchromatography to provide2′-chloro-7′,8′-dihydro-6′H-spiro[cyclohexane-1,9′-pyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyrimidine]-6′-thione(12, 1.0 g, 3.2 mmol). MS (ESI): m/z 307 [M+H]⁺.

Step 4: Synthesis of2′-Chloro-6′-(methylthio)-8′H-spiro[cyclohexane-1,9′-pyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyrimidine](13)

To a solution of2′-chloro-7′,8′-dihydro-6′H-spiro[cyclohexane-1,9′-pyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyrimidine]-6′-thione(12, 60 mg, 0.20 mmol) in acetone (5 mL) was added CH₃I (100 mg, 0.70mmol) and K₂CO₃ (50 mg, 0.36 mmol). After stirred at room temperatureovernight, the reaction mixture was concentrated in vacuo. The resultingresidue was purified by column chromatography to provide2′-chloro-6′-(methylthio)-8′H-spiro[cyclohexane-1,9′-pyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyrimidine] (13, 60 mg, 0.19 mmol). MS (ESI+): m/z 321[M+H]⁺.

Step 5: Synthesis ofN-(5-(4-Methylpiperazin-1-yl)pyridin-2-yl)-6′-(methylthio)-8′H-spiro[cyclohexane-1,9′-pyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyrimidin]-2′-amine(14)

Under N₂ atmosphere, to a mixture of2′-chloro-6′-(methylthio)-8′H-spiro[cyclohexane-1,9′-pyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyrimidine] (13, 60 mg, 0.19 mmol),5-(4-methylpiperazin-1-yl)pyridin-2-amine (36 mg, 0.19 mmol), Pd₂(dba)₃(29 mg, 0.03 mmol) and BINAP (29 mg, 0.05 mmol) in toluene (2 mL) wasadded LHMDS (0.30 mL, 0.3 mmol, 1 M in THF). After stirring at 100° C.for 24 h, the reaction mixture was cooled to room temperature, quenchedwith aqueous NH₄Cl (5 mL) and extracted with EtOAc (5 mL). The organicphase was separated and concentrated in vacuo. The resulting residue waspurified by prep TLC to affordN-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)-6′-(methylthio)-8′H-spiro[cyclohexane-1,9′-pyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyrimidin]-2′-amine (14, 30 mg, 0.06 mmol). MS (ESI+):m/z 477 [M+H]⁺.

Step 6: Synthesis ofN²′-(5-(4-Methylpiperazin-1-yl)pyridin-2-yl)-N⁶′-propyl-8′H-spiro[cyclohexane-1,9′-pyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyrimidine]-2′,6′-diamine (Compound 3)

To a solution ofN-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)-6′-(methylthio)-8H-spiro[cyclohexane-1,9′-pyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyrimidin]-2′-amine (14, 30 mg, 0.02 mmol) in toluene(5 mL) was added propan-1-amine (15 mg, 0.25 mmol). After stirred underreflux overnight, the reaction mixture was cooled to room temperatureand concentrated in vacuo. The resulting residue was purified by prepTLC to affordN2′-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)-N6′-propyl-8′H-spiro[cyclohexane-1,9′-pyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyrimidine]-2′,6′-diamine (COMPOUND 3, 7.8 mg, 0.016mmol). MS (ESI+): m/z 488 [M+H]⁺; ¹H NMR (300 MHz, MeOD): δ 8.96 (s,1H), 8.11 (d, J=9.0 Hz, 1H), 8.07 (d, J=2.7 Hz, 1H), 7.64 (s, 1H), 7.60(dd, J=9.0, 3.0 Hz, 1H), 3.94 (s, 2H), 3.48-3.40 (m, 6H), 3.31-3.22 (m,3H), 3.13-3.04 (m, 2H), 2.83 (s, 3H), 2.02-1.88 (m, 6H), 1.85-1.78 (m,2H), 1.66-1.49 (m, 3H), 1.09 (t, J=7.5 Hz, 3H).

To a solution ofN-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)-6′-(methylthio)-8′H-spiro[cyclohexane-1,9′-pyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyrimidin]-2′-amine (15, 50 mg, 0.10 mmol) in i-PrOH(3 mL) was added aniline (50 mg, 0.53 mmol) and HOAc (3 drops). Afterstirring under reflux for 3 h, the reaction mixture was cooled to roomtemperature and concentrated in vacuo. The resulting residue waspurified by prep TLC to affordN2′-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)-N6′-phenyl-8′H-spiro[cyclohexane-1,9′-pyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyrimidine]-2′,6′-diamine (COMPOUND 4, 16.9 mg, 0.032mmol). MS (ESI+): m/z 522 [M+H]⁺; ¹H NMR (300 MHz, MeOD): δ8.99 (s, 1H),8.23 (d, J=9.0 Hz, 1H), 8.07 (d, J=2.7 Hz, 1H), 7.85 (s, 1H), 7.62-7.57(m, 2H), 7.50-7.43 (m, 4H), 3.88 (s, 2H), 3.48-3.45 (m, 4H), 3.27-3.21(m, 4H), 3.09 (t, J=12.3 Hz, 2H), 2.80 (s, 3H), 2.02-1.90 (m, 5H),1.56-1.44 (m, 3H).

To a solution ofN-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)-6′-(methylthio)-8′H-spiro[cyclohexane-1,9′-pyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyrimidin]-2′-amine (15, 50 mg, 0.10 mmol) in toluene(3 mL) was added excess benzylamine. After stirring under reflux for 24h, the reaction mixture was cooled to room temperature and concentratedin vacuo. The resulting residue was purified by prep TLC to affordN6′-benzyl-N2′-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)-8′H-spiro[cyclohexane-1,9′-pyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyrimidine]-2′,6′-diamine (COMPOUND 5, 24.2 mg, 0.045mmol). MS (ESI+): m/z 536 [M+H]⁺; ¹H NMR (300 MHz, MeOD+CDCl₃): δ 8.91(s, 1H), 8.22 (d, J=9.0 Hz, 1H), 8.04 (d, J=2.7 Hz, 1H), 7.73 (s, 1H),7.45-7.36 (m, 6H), 4.77 (s, 2H), 3.89 (s, 2H), 3.46-3.41 (m, 4H),3.22-3.14 (m, 4H), 3.10-3.00 (m, 2H), 2.76 (s, 3H), 1.99-1.88 (m, 5H),1.63-1.43 (m, 3H).

To a solution of 2′-chloro-8′H-spiro[cyclohexane-1,9′-pyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyrimidine] (16, 80 mg, 0.29 mmol),(1r,4r)-cyclohexane-1,4-diamine (16, 160 mg, 1.40 mmol) in EtOH (3 mL)was added TEA (0.5 mL). The reaction was kept at 140° C. overnight.After cooled to room temperature, the mixture was concentrated in vacuoto afford the residue, which was purified by prep TLC to afford(1r,4r)-N¹-(8′H-spiro[cyclohexane-1,9′-pyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyrimidin]-2′-yl)cyclohexane-1,4-diamine (COMPOUND 6,25.0 mg, 0.07 mmol). MS (ESI+): m/z 353 [M+H]⁺; ¹H NMR (300 MHz, MeOD):δ 8.59 (s, 1H), 8.36 (s, 1H), 6.85 (s, 1H), 4.01 (s, 2H), 3.82-3.75 (m,1H), 3.21-3.14 (m, 1H), 2.91 (td, J=13.2, 3.9 Hz, 2H), 2.34-2.18 (m,4H), 1.87-1.78 (m, 5H), 1.66-1.27 (m, 7H).

A solution ofN-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)-6′-(methylthio)-8′H-spiro[cyclohexane-1,9′-pyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyrimidin]-2′-amine (15, 25 mg, 0.05 mmol) and(1R,4R)-cyclohexane-1,4-diamine (1 mL) in NMP (2 mL) was stirred at 165°C. for 6 h. The reaction mixture was cooled to room temperature,quenched with water (10 mL) and extracted with EtOAc (10 mL×3). Thecombined organic phases were dried over Na₂SO₄, filtered andconcentrated to in vacuo. The resulting residue was purified by columnchromatography to provideN⁶′-((1R,4R)-4-aminocyclohexyl)-N²′-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)-8′H-spiro[cyclohexane-1,9′-pyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyrimidine]-2′,6′-diamine (COMPOUND 7, 5.1 mg, 0.0094mmol). MS (ESI+): m/z 543 [M+H]⁺; ¹HNMR (300 MHz, MeOD): δ 8.86 (s, 1H),8.02-7.96 (m, 2H), 7.64 (s, 1H), 7.53 (d, J=8.1 Hz, 1H), 3.85 (s, 2H),3.76 (m, 1H), 3.46-3.25 (m, 6H), 3.14-3.04 (m, 2H), 3.03-2.88 (m, 3H),2.86 (s, 3H), 2.18-1.95 (m, 5H), 1.93-1.71 (m, 6H), 1.66-1.49 (m, 5H).

A solution ofN-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)-6′-(methylthio)-8′H-spiro[cyclohexane-1,9′-pyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyrimidin]-2′-amine (15, 25 mg, 0.05 mmol) inpiperidine (2 mL) was stirred at 120° C. for 6 h. The reaction mixturewas cooled to room temperature, quenched with water (10 mL) andextracted with EtOAc (10 mL×3). The combined organic phases were driedover Na₂SO₄, filtered and concentrated in vacuo. The resulting residuewas purified by column chromatography to provideN-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)-6′-(piperidin-1-yl)-8′H-spiro[cyclohexane-1,9′-pyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyrimidin]-2′-amine(COMPOUND 8, 7.9 mg, 0.015 mmol). MS (ESI+): m/z 514 [M+H]⁺; ¹H NMR (300MHz, MeOD): δ 8.94 (s, 1H), 8.08-8.04 (m, 2H), 7.52 (dd, J=9.0, 3.0 Hz,1H), 7.46 (s, 1H), 3.87-3.80 (m, 6H), 3.27 (t, J=4.8 Hz, 4H), 3.04 (t,J=10.5 Hz, 2H), 2.74 (t, J=4.8 Hz, 4H), 2.44 (s, 3H), 2.03-1.87 (m,11H), 1.66-1.48 (m, 3H).

Step 1: Synthesis of Di-tert-butyl((1-(2-chloro-6-(diethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexyl)methyl)carbamate(18)

To a solution of tert-butyl((1-(2-chloro-6-(diethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexyl)methyl)carbamate(17, 2.0 g, 4.2 mmol) in THF (25 mL) was added DMAP (3.0 g, 24.5 mmol)and (Boc)₂O (2.0 g, 9.2 mmol). The reaction was refluxed for 2 h. Aftercooling to room temperature, the reaction mixture was concentrated invacuo. The resulting residue was purified by column chromatography witha gradient elution of hexane (100%) to hexane (80%) and EtOAc (20%) toprovide di-tert-butyl((1-(2-chloro-6-(diethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexyl)methyl)carbamate(18, 1.5 g, 2.6 mmol). MS (ESI+): m/z 567 [M+H]⁺.

Step 2: Synthesis of Di-tert-butyl((1-(2-chloro-6-formyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexyl)methyl)carbamate (19)

To a solution of di-tert-butyl((1-(2-chloro-6-(diethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexyl)methyl)carbamate(17, 600 mg, 1.0 mmol) in THF/H2O (2 mL/2 mL) was added HOAc (2 mL). Thereaction was stirred at 60° C. overnight. After cooling to roomtemperature, the reaction mixture was neutralized with NaHCO₃ to PH 7.0and extracted with EtOAc (20 mL×2). The combined organic phases wereconcentrated in vacuo to afford the residue, which was purified bycolumn chromatography to afford di-tert-butyl((1-(2-chloro-6-formyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexyl)methyl)carbamate(19, 400 mg, 0.8 mmol). MS (ESI): m/z 493 [M+H]⁺.

Step 3: Synthesis of Di-tert-butyl((1-(2-chloro-6-(1-hydroxyethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexyl)methyl)carbamate (20)

Under N₂ atmosphere, to a solution of di-tert-butyl((1-(2-chloro-6-formyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexyl)methyl)carbamate(19, 400 mg, 0.8 mmol) in anhydrous THF (20 mL) at −78° C. was addedmethyl magnesium bromide (6 mL, 6 mmol, 1M in THF). After completion ofthe addition, the reaction mixture was continued to stir for 10 min andthen quenched with 5 mL of ammonium chloride aqueous solution. Theaqueous solution was extracted with EtOAc (20 mL×2). The organic layerswere separated and concentrated in vacuo to afford the residue, whichwas purified by column chromatography with a gradient elution of hexane(95%) and EtOAc (5%) to hexane (80%) and EtOAc (20%) to providedi-tert-butyl((1-(2-chloro-6-(1-hydroxyethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexyl)methyl)carbamate(20, 320 mg, 0.6 mmol). MS (ESI+): m/z 509 [M+H]⁺.

Step 4: Synthesis of Di-tert-butyl((1-(6-acetyl-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexyl)methyl)carbamate (21)

To a solution of di-tert-butyl((1-(2-chloro-6-(1-hydroxyethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexyl)methyl)carbamate(20, 320 mg, 0.6 mmol) in DCM (5 mL) was added Dess-Martin periodinane(305 mg, 0.72 mmol). After stirring at room temperature for 3 h, thereaction mixture was neutralized with 5 mL of saturated sodiumbicarbonate solution and stirred for 1 h. The precipitated solid wasremoved by filtration and the filtrate was extracted with DCM (5 mL×2).The combined organic phases were concentrated in vacuo to afford theresidue, which was purified by column chromatography with a gradientelution hexane (95%) and EtOAc (5%) to hexane (80%) and EtOAc (20%) toprovide di-tert-butyl((1-(6-acetyl-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexyl)methyl)carbamate(21, 200 mg, 0.4 mmol). MS (ESI+): m/z 507 [M+H]⁺.

Step 5: Synthesis of2′-Chloro-6′-methyl-8′H-spiro[cyclohexane-1,9′-pyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyrimidine](22)

To a solution of di-tert-butyl((1-(6-acetyl-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexyl)methyl)carbamate(21, 200 mg, 0.4 mmol) in DCM (11 mL) at 5° C. was added TFA (1.1 mL).After stirring at room temperature for 3 h, the reaction mixture wasquenched with 5 mL of saturated sodium bicarbonate solution andextracted with DCM (10 mL×2). The combined organic phases wereconcentrated in vacuo to afford the residue, which was purified bycolumn chromatography with a gradient elution hexane (95%) and EtOAc(5%) to hexane (80%) and EtOAc (20%) to afford2′-chloro-6′-methyl-8′H-spiro[cyclohexane-1,9′-pyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyrimidine](22, 25 mg, 0.09 mmol). MS (ESI+): m/z 289 [M+H]⁺.

Step 6: Synthesis of6′-Methyl-N-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)-8′H-spiro[cyclohexane-1,9′-pyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyrimidin]-2′-amine (Compound 9)

Under N₂ atmosphere, to a solution of2′-chloro-6′-methyl-8′H-spiro[cyclohexane-1,9′-pyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyrimidine](22, 25 mg, 0.09 mmol) and 5-(4-methylpiperazin-1-yl)pyridin-2-amine (17mg, 0.09 mmol) in anhydrous 1,4-dioxane (5 mL) was added Pd(OAc)₂ (4 mg,0.02 mmol), X-phos (10 mg, 0.02 mmol) and Cs₂CO₃ (60 mg, 0.18 mmol). Thereaction mixture was stirred at 110° C. overnight. After cooling to roomtemperature, the reaction mixture was quenched with water (10 mL) andextracted with EtOAc (20 mL). The organic layer was separated andconcentrated in vacuo to afford the residue, which was purified by prepTLC to provide6′-methyl-N-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)-8′H-spiro[cyclohexane-1,9′-pyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyrimidin]-2′-amine (COMPOUND 9, 3.1 mg, 0.007 mmol).MS (ESI+): m/z 445 [M+H]⁺; ¹H NMR (300 MHz, MeOD): δ 8.86 (s, 1H), 8.18(d, J=9.3 Hz, 1H), 8.02 (d, J=3.0 Hz, 1H), 7.52 (dd, J=9.0, 3.0 Hz, 1H),7.15 (s, 1H), 4.03 (s, 2H), 3.46-3.40 (m, 4H), 3.22-3.15 (m, 4H), 2.95(td, J=13.2, 4.2 Hz, 2H), 2.76 (s, 3H), 2.52 (s, 3H), 1.93-1.84 (m, 5H),1.68-1.55 (m, 2H), 1.48-1.40 (m, 1H).

Step 1: Synthesis of 4-Aminotetrahydro-2H-pyran-4-carbonitrile (24)

Under N₂ atmosphere, to a solution of Ti(O-iPr)₄ (23, 68 g, 239 mmol) inNH₃/EtOH (300 mL) at room temperature was addedtetrahydro-4H-pyran-4-one (260, 20 g, 200 mmol). After stirring at 20°C. for 2 h, the reaction was cooled to −5° C. TMSCN (20.6 g, 208 mmol)was added dropwise and the reaction was continued to stir at −5° C. for3 h. The reaction was then warmed to room temperature and stirred for 12h. The reaction mixture was quenched with water (20 mL), filtered, andthe filter cake was washed with EtOH (20 mL×2). The filtrate wasconcentrated in vacuo. The resulting residue was purified by columnchromatography to provide 4-aminotetrahydro-2H-pyran-4-carbonitrile (24,260, 20.8 g, 165 mmol) as a yellow oil.

Step 2: Synthesis of 4-(Aminomethyl)tetrahydro-2H-pyran-4-amine (25)

To a suspension of LiAlH₄ (9.1 g, 240 mmol) in MTBE (120 mL) at roomtemperature was added 4-aminotetrahydro-2H-pyran-4-carbonitrile (24,261, 10 g, 80 mmol). After stirring at 40° C. for 2 h, the reactionmixture was quenched with water (9.1 mL) and 15% aqueous NaOH (9.1 mL),followed by the addition of water (27.3 mL). After stirring for 1 h, themixture was filtered and the filter cake was washed with MTBE (20 mL×2).The filtrate was concentrated in vacuo to provide4-(aminomethyl)tetrahydro-2H-pyran-4-amine (25, 6 g, 46.1 mmol), whichwas carried forward in the next step without further purification.

Step 3: Synthesis of tert-Butyl((4-aminotetrahydro-2H-pyran-4-yl)methyl)carbamate (26)

Under N₂ atmosphere, to a solution of4-(aminomethyl)tetrahydro-2H-pyran-4-amine (25, 6 g, 46.1 mmol) in DCM(230 mL) at −78° C. was added Boc₂O (8.5 g, 39 mmol) dropwise over 1 h.After stirring at −78° C. for an additional 2 h, the reaction wasgradually warmed to room temperature. 1 M HCl was added to adjust pH=5.The aqueous phase was extracted with EtOAc (200 mL). The aqueous phasewas collected and adjusted to pH=10 with 15% aqueous NaOH and extractedwith DCM (200 mL×3). The combined organic phases were dried over Na₂SO₄,filtered and concentrated to provide tert-butyl((4-aminotetrahydro-2H-pyran-4-yl)methyl)carbamate (26, 6.05 g, 26.3mmol).

Step 4: Synthesis of tert-Butyl((4-((2-chloro-5-iodopyrimidin-4-yl)amino)tetrahydro-2H-pyran-4-yl)methyl)carbamate (28)

To a solution of 2,4-dichloro-5-iodopyrimidine (27, 8.7 g, 31.6 mmol)and tert-butyl ((4-aminotetrahydro-2H-pyran-4-yl)methyl)carbamate (26, 5g, 21.7 mmol) in DMAc (200 mL) was added NaHCO₃(11.1 g, 132 mmol). Afterstirring at 80° C. for 12 h, the reaction mixture was quenched withwater (50 mL) and extracted with EtOAc (300 mL×3). The combined organicphases were washed with water (200 mL×2) and brine (100 mL), dried overNa₂SO₄, filtered and concentrated in vacuo. The resulting residue waspurified by column chromatography to provide tert-butyl((4-((2-chloro-5-iodopyrimidin-4-yl)amino)tetrahydro-2H-pyran-4-yl)methyl)carbamate (28, 5.02 g, 10.7 mmol).

Step 5: Synthesis of tert-Butyl((4-((2-chloro-5-(3,3-diethoxyprop-1-yn-1-yl)pyrimidin-4-yl)amino)tetrahydro-2H-pyran-4-yl)methyl)carbamate (29)

Under N₂ atmosphere, to a solution oftert-butyl((4-((2-chloro-5-iodopyrimidin-4-yl)amino)tetrahydro-2H-pyran-4-yl) methyl)carbamate (28, 5.70 g, 12.2 mmol) andDIEA (3.11 g, 24.1 mmol) in THF (170 mL) was added CuI (228 mg, 1.2mmol) and Pd(PPh₃)₂Cl₂ (342 mg, 0.49 mmol). After stirring at roomtemperature for 10 min, 3,3-diethoxyprop-1-yne (1.9 g, 14.8 mmol) in THF(5 mL) was added dropwise and the reaction was stirred at roomtemperature for 12 h. The reaction was quenched with water (20 mL) andextracted with EtOAc (20 mL×2). The combined organic phases wereconcentrated in vacuo. The resulting residue was purified by columnchromatography to provide tert-butyl((4-((2-chloro-5-(3,3-diethoxyprop-1-yn-1-yl)pyrimidin-4-yl)amino)tetrahydro-2H-pyran-4-yl)methyl)carbamate(29, 5.03 g, 10.7 mmol). MS (ESI+): m/z 469 [M+H]⁺.

Step 6: Synthesis of tert-Butyl((4-(2-chloro-6-(diethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydro-2H-pyran-4-yl)methyl)carbamate (30)

To a solution of tert-butyl((4-((2-chloro-5-(3,3-diethoxyprop-1-yn-1-yl)pyrimidin-4-yl)amino)tetrahydro-2H-pyran-4-yl)methyl)carbamate(29, 4.90 g, 10.4 mmol) in THF (50 mL) was added TBAF (50 mL, 50 mmol, 1M in THF). After stirring at 65° C. for 2 h, the reaction was cooled toroom temperature and quenched with water (150 mL). The aqueous solutionwas extracted with EtOAc (100 mL×3). The combined organic phases weredried over Na₂SO₄, filtered and concentrated in vacuo. The resultingresidue was purified by column chromatography to provide tert-butyl((4-(2-chloro-6-(diethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydro-2H-pyran-4-yl)methyl)carbamate(30, 1.8 g, 3.84 mmol). MS (ESI+): m/z 491 [M+Na]⁺.

Step 7: Synthesis of tert-Butyl ((4-(2-chloro-6-formyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydro-2H-pyran-4-yl)methyl)carbamate (31)

To a solution of tert-butyl((4-(2-chloro-6-(diethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydro-2H-pyran-4-yl)methyl)carbamate(30, 800 mg, 1.71 mmol) in THF (4 mL) was added water (4 mL) and AcOH (4mL). After stirring at 60° C. for 2 h, the reaction mixture wasneutralized with saturated aqueous NaHCO₃ and extracted with EtOAc (100mL×3). The combined organic phases were dried over Na₂SO₄ andconcentrated in vacuo. The resulting residue was purified by columnchromatography to provide tert-butyl((4-(2-chloro-6-formyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydro-2H-pyran-4-yl)methyl)carbamate(31, 527 mg, 1.33 mmol).

Step 8: Synthesis of2′-Chloro-2,3,5,6-tetrahydro-8′H-spiro[pyran-4,9′-pyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyrimidine](32)

To a solution of tert-butyl((4-(2-chloro-6-formyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydro-2H-pyran-4-yl)methyl)carbamate(31, 80 mg, 0.20 mmol) in DCM (5 mL) at 0° C. was added TFA (0.15 mL).After stirring at room temperature for 2 h, the reaction mixture wasneutralized with saturated aqueous NaHCO₃ and extracted with DCM (50mL×3). The combined organic phases were dried over Na₂SO₄, filtered andconcentrated in vacuo. The resulting residue was purified by columnchromatography to provide2′-chloro-2,3,5,6-tetrahydro-8′H-spiro[pyran-4,9′-pyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyrimidine] (32, 13 mg, 0.05 mmol). MS (ESI+): m/z 277[M+H]⁺.

Step 9: Synthesis ofN-(5-(4-Methylpiperazin-1-yl)pyridin-2-yl)-2,3,5,6-tetrahydro-8′H-spiro[pyran-4,9′-pyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyrimidin]-2′-amine(Compound 10)

Under N₂ atmosphere, to a solution of2′-chloro-2,3,5,6-tetrahydro-8′H-spiro[pyran-4,9′-pyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyrimidine] (32, 50 mg, 0.18 mmol) and5-(4-methylpiperazin-1-yl)pyridin-2-amine (52 mg, 0.27 mmol) in dioxane(4 mL) was added Cs₂CO₃ (170 mg, 0.52 mmol), Pd(OAc)₂ (8 mg, 0.04 mmol)and X-Phos (12 mg, 0.03 mmol). After stirring at 100° C. for 12 h, themixture was directly concentrated in vacuo. The resulting residue waspurified by prep TLC to provideN-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)-2,3,5,6-tetrahydro-8′H-spiro[pyran-4,9′-pyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyrimidin]-2′-amine (COMPOUND 10, 20 mg, 0.05 mmol).MS (ESI+): m/z 433 [M+H]⁺; ¹H NMR (300 MHz, MeOD): δ 8.90 (s, 1H), 8.53(s, 1H), 8.09 (d, J=9.0 Hz, 1H), 8.03 (d, J=3.0 Hz, 1H), 7.70 (d, J=7.2Hz, 1H), 7.09 (s, 1H), 4.24 (d, J=1.7 Hz, 2H), 4.01 (dd, J=12.3, 4.8 Hz,2H), 3.77 (t, J=11.8 Hz, 2H), 3.56-3.33 (m, 8H), 3.28-3.17 (m, 2H), 2.95(s, 3H), 1.82 (d, J=13.6 Hz, 2H).

Step 1: Synthesis of(1R,4R)-2′-Chloro-4-methoxy-8′H-spiro[cyclohexane-1,9′-pyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyrimidine](34)

To a solution of tert-butyl (((1R,4R)-1-(2-chloro-6-formyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-4-methoxycyclohexyl)methyl)carbamate (33, 300 mg,0.71 mmol) in DCM (20 mL) at 0° C. was added TFA (0.9 mL). After thereaction was stirred for 2 h, saturated NaHCO₃ solution was added toadjust pH to approximately 7-8. The aqueous phase was extracted with DCM(50 mL×3). The organic layer was dried over Na₂SO₄ and concentrated toafford the residue, which was purified by silica column chromatography(MeOH/DCM=1:20) to provide(1R,4R)-2′-chloro-4-methoxy-8′H-spiro[cyclohexane-1,9′-pyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyrimidine] (34, 95 mg, 0.31 mmol). MS (ESI+): m/z 305[M+H]⁺.

Step 2: Synthesis of(1R,4R)-4-Methoxy-N-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)-8′H-spiro[cyclohexane-1,9′-pyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyrimidin]-2′-amine (Compound 12)

Under N₂ atmosphere, to a solution of(1R,4R)-2′-chloro-4-methoxy-8′H-spiro[cyclohexane-1,9′-pyrazino[1′,2′:1,5] pyrrolo[2,3-d]pyrimidine] (34, 95 mg, 0.31 mmol),5-(4-methylpiperazin-1-yl)pyridin-2-amine (66 mg, 0.34 mmol) and Cs₂CO₃(203 mg, 0.62 mmol) in dioxane (5 mL) was added Pd(OAc)₂ (7 mg, 0.03mmol) and X-Phos (59 mg, 0.12 mmol). After stirring for 12 h at 100° C.,the reaction mixture was concentrated to afford the residue, which waspurified by silica column chromatography (MeOH/DCM=1:5) to provide(1R,4R)-4-methoxy-N-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)-8′H-spiro[cyclohexane-1,9′-pyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyrimidin]-2′-amine.(COMPOUND 12, 18.9 mg, 0.04 mmol). MS (ESI+): m/z 461 [M+H]⁺; ¹H NMR(300 MHz, MeOD): δ 8.80 (s, 1H), 8.42 (s, 1H), 8.37 (d, J=9.0 Hz, 1H),8.03 (d, J=2.9 Hz, 1H), 7.56 (dd, J=9.2, 3.0 Hz, 1H), 6.94 (s, 1H), 4.07(d, J=1.6 Hz, 2H), 3.58 (s, 1H), 3.42-3.36 (m, 4H), 3.35 (s, 3H),3.26-3.13 (m, 6H), 2.77 (s, 3H), 2.11-2.00 (m, 2H), 1.83-1.68 (m, 2H),1.68-1.58 (m, 2H).

Step 1: Synthesis of(1S,4S)-2′-Chloro-4-methoxy-8′H-spiro[cyclohexane-1,9′-pyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyrimidine(36)

To a solution of tert-butyl (((1S,4S)-1-(2-chloro-6-formyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-4-methoxycyclohexyl)methyl)carbamate(35, 300 mg, 0.71 mmol) in DCM (20 mL) at 0° C. was added TFA (0.9 mL)dropwise. After stirring at 0° C. for 2 h, the reaction mixture wasquenched with saturated aqueous NaHCO₃ and extracted with DCM (50 mL×3).The combined organic phases were dried over Na₂SO₄, filtered andconcentrated in vacuo. The resulting residue was purified by columnchromatography to provide(1S,4S)-2′-chloro-4-methoxy-8′H-spiro[cyclohexane-1,9′-pyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyrimidine] (100 mg, 0.33 mmol). MS (ESI+): m/z 305[M+H]⁺.

Step 2: Synthesis of(1S,4S)-4-Methoxy-N-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)-8′H-spiro[cyclohexane-1,9′-pyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyrimidin]-2′-amine (Compound 13)

Under N₂ atmosphere, to a solution of(1S,4S)-2′-chloro-4-methoxy-8′H-spiro[cyclohexane-1,9′-pyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyrimidine] (36, 100 mg, 0.33 mmol),5-(4-methylpiperazin-1-yl)pyridin-2-amine (76 mg, 0.39 mmol) in dioxane(5 mL) was added Cs₂CO₃ (320 mg, 0.98 mmol), Pd(OAc)₂ (7.4 mg, 0.03mmol) and X-Phos (62 mg, 0.13 mmol). After stirring at 100° C. for 12 h,the reaction was cooled to room temperature, quenched with water (10 mL)and extracted with EtOAc (10 mL×2). The combined organic phases wereconcentrated in vacuo. The resulting residue was purified by prep TLC toprovide(1S,4S)-4-methoxy-N-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)-8′H-spiro[cyclohexane-1,9′-pyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyrimidin]-2′-amine(COMPOUND 13, 21.2 mg, 0.04 mmol). MS (ESI+): m/z 461 [M+H]⁺; ¹H NMR(300 MHz, MeOH+CDCl₃): δ 9.00 (s, 1H), 8.60 (s, 1H), 8.36 (d, J=9.2 Hz,1H), 8.20 (s, 1H), 7.66 (d, J=8.8 Hz, 1H), 7.06 (s, 1H), 4.30 (s, 2H),3.66 (s, 3H), 3.64-3.55 (m, 5H), 3.33-3.14 (m, 3H), 3.14-3.02 (m, 3H),2.76 (s, 3H), 2.44-2.32 (m, 2H), 2.22-2.11 (m, 2H), 1.85-1.70 (m, 2H).

Example 3. Non-Limiting Examples of Compounds

Table 1 shows illustrative Compounds. Experimental details andcharacterizing data are provided in Example 2.

Compd # Compound Structure 1

2

3

4

5

6

7

8

9

10

11

12

13

Example 4: CDK4/6 Inhibition In Vitro Assay

Selected compounds disclosed herein were tested in CDK4/cyclinD1,CDK2/CycA and CDK2/cyclinE kinase assays by Nanosyn (Santa Clara,Calif.) to determine their inhibitory effect on these CDKs. The assayswere performed using microfluidic kinase detection technology (CaliperAssay Platform). The compounds were tested in 12-point dose-responseformat in singlicate at Km for ATP. Phosphoacceptor substrate peptideconcentration used was 1 μM for all assays and Staurosporine was used asthe reference compound for all assays. Specifics of each assay are asdescribed below:

CDK2/CyclinA: Enzyme concentration: 0.2 nM; ATP concentration: 50 μM;Incubation time: 3 hr.

CDK2/CyclinE: Enzyme concentration: 0.28 nM; ATP concentration: 100 μM;Incubation time: 1 hr.

CDK4/CyclinD1: Enzyme concentration: 1 nM; ATP concentration: 200 μM;Incubation time: 10 hr.

TABLE 2 Biological Data of Selected Compounds CDK4/ CDK6/ CDK2/ CDK2/CDK9/ Compd Cyclin Cyclin Cyclin E Cyclin Cyclin T # Compound StructureD1 (μM) D3 (μM) (μM) A (μM) (μM) 1

0.001 0.003 0.061 0.187 0.095 2

0.029 0.09 5.75 12.9 4.47 3

0.74 1.26 >100 >100 32.5 4

0.027 0.061 54.9 24.6 1.57 5

0.16 0.39 >100 70.7 11.2 9

0.096 0.024 3.0 3.7 2.5 10

0.04 0.07 5 7 2 12

0.04 0.1 7 10 1 13

0.009 0.02 3 4 0.9

All publications and patent applications cited in this specification areherein incorporated by reference as if each individual publication orpatent application were specifically and individually indicated to beincorporated by reference.

The descriptions herein are described by way of illustration and examplefor purposes of clarity of understanding for embodiments only. It willbe readily apparent to one of ordinary skill in the art in light of theteachings of this invention that certain changes and modifications maybe made thereto without departing from the spirit or scope of theinvention as defined in the appended claims.

I claim:
 1. A compound of Formula:

or a pharmaceutically acceptable salt thereof; wherein: y is 0, 1, 2, 3,or 4; Z is S, CH₂, CHR¹², CR¹²R¹³, NH, or NR¹²;

represents the presence or absence of a double bond; R is hydrogen,C₁-C₆alkyl, —(C₀-C₂alkyl)(C₃-C₈carbocyclyl),—(C₀-C₂alkyl)(C₃-C₈heterocyclyl),—(C₀-C₂alkyl)(aryl),—(C₀-C₂alkyl)(heteroaryl), —COOalkyl, —COOarylalkyl, or —COOH; each R¹is independently at each occurrence selected from the group consistingof alkyl, aryl, cycloalkyl, and haloalkyl, wherein each of said alkyl,cycloalkyl and haloalkyl groups optionally includes heteroatoms O, N, orS in place of a carbon in the chain and two R¹s on adjacent ring atomsor on the same ring atom together with the ring atom(s) to which theyare attached optionally form a 3-8-membered cycle; wherein the 3-8membered cycle formed by combining two R¹s with the atom(s) to whichthey are attached can be either a carbocycle or a heterocycle; andwherein the 3-8 membered cycle formed by combining two R¹s with theatom(s) to which they are attached can be optionally substituted withone or more substituents selected from the group consisting of amino,—NHR¹⁴, —NR¹⁴R¹⁵, hydroxyl, OR¹⁴, R⁶, and R²; R⁷ is selected from thegroup consisting of:

or R⁷ is selected from the group consisting of cycloalkyl, heterocycle,and alkyl, each of which cycloalkyl, heterocycle, and alkyl groups isoptionally substituted with one or more substituents selected from thegroup consisting of amino, —NHR¹⁴, —NR¹⁴R¹⁵, hydroxyl, OR¹⁴, R⁶, and R²;X¹, X², X³, X⁴, and X⁵ are independently N or CR⁸, wherein at least oneof X¹, X², X³, X⁴, and X⁵ are CR⁸; R⁸ is independently at each instanceselected from the group consisting of R⁶ and R², wherein one R⁸ is R²;R² is independently selected from the group consisting of-(alkylene)_(m)-heterocyclo, -(alkylene)_(m)-hetero aryl,-(alkylene)_(m)-NR³R⁴, -(alkylene)_(m)-C(O)—NR³R⁴;-(alkylene)_(m)-C(O)—O-alkyl; -(alkylene)_(m)-O—R⁵,-(alkylene)_(m)-S(O)_(n)—R⁵, and -(alkylene)_(m)-S(O)_(n)—NR³R⁴; any ofwhich may be optionally independently substituted with one or more R^(x)groups as allowed by valance, and wherein two R^(x) groups bound to thesame or adjacent atom may optionally combine to form a ring; m is 0 or1; n is 0, 1 or 2; R³ and R⁴ at each occurrence are independentlyselected from the group consisting of hydrogen, alkyl, cycloalkyl,heterocyclo, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl,arylalkyl, and heteroarylalkyl; or R³ and R⁴ together with the nitrogenatom to which they are attached may combine to form a heterocyclo ring;R⁵ is independently at each occurrence selected from the groupconsisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,heterocyclo, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl,arylalkyl, and heteroarylalkyl; R^(x) at each occurrence isindependently selected from the group consisting of halo, cyano, nitro,oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl,heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl,heterocycloalkyl, -(alkylene)_(m)-OR⁵, -(alkylene)_(m)-O-alkylene-OR⁵,-(alkylene)_(m)-S(O)_(n)—R⁵, -(alkylene)_(m)-NR³R⁴, -(alkylene)_(m)-CN,-(alkylene)_(m)-C(O)—R⁵, -(alkylene)_(m)-C(S)—R⁵,-(alkylene)_(m)-C(O)—OR⁵, -(alkylene)_(m)-O—C(O)—R⁵,-(alkylene)_(m)-C(S)—OR⁵, -(alkylene)_(m)-C(O)-(alkylene)_(m)-NR³R⁴,-(alkylene)_(m)-C(S)—NR³R⁴, -(alkylene)_(m)-N(R³)—C(O)—NR³R⁴,-(alkylene)_(m)-N(R³)—C(S)—NR³R⁴, -(alkylene)_(m)-N(R³)—C(O)—R⁵,-(alkylene)_(m)-N(R³)—C(S)—R⁵, -(alkylene)_(m)-O—C(O)—NR³R⁴,-(alkylene)_(m)-O—C(S)—NR³R⁴, -(alkylene)_(m)-SO₂—NR³R⁴,-(alkylene)_(m)-N(R³)—SO₂—R⁵, -(alkylene)_(m)-N(R³)—SO₂—NR³R⁴,-(alkylene)_(m)-N(R³)—C(O)—OR⁵, -(alkylene)_(m)-N(R³)—C(S)—OR⁵, and-(alkylene)_(m)-N(R³)—SO₂—R⁵, R⁶ is independently at each instanceselected from the group consisting of hydrogen, halogen, alkyl, alkenyl,alkynyl cycloalkyl, heterocyclo, aryl, heteroaryl, cycloalkylalkyl,heterocycloalkyl, arylalkyl, and heteroarylalkyl; R¹⁰ and R¹¹ areselected from the group consisting of hydrogen, alkyl, —NH₂, —NHR¹²,—NR¹²R¹³, —S(O)alkyl, and —SO₂alkyl; or R¹⁰ and R¹¹ are selected fromthe group consisting of cycloalkyl, heterocycle, aryl, heteroaryl,arylalkyl, and heteroarylalkyl, each of which is optionally substitutedwith one or more substituents selected from the group consisting ofamino, —NHR¹⁴, —NR¹⁴R¹⁵, hydroxyl, OR¹⁴, R⁶, and R²; R¹² is selectedfrom the group consisting of hydrogen, alkyl, alkenyl, alkynyl, —C(O)H,—C(O)alkyl, —C(S)alkyl, aryl, —SO₂alkyl, heteroaryl, arylalkyl, andheteroarylalkyl; or R¹² is selected from the group consisting ofcycloalkyl, heterocycle, aryl, heteroaryl, arylalkyl, andheteroarylalkyl, each of which is optionally substituted with one ormore substituents selected from the group consisting of amino, —NHR¹⁴,—NR¹⁴R¹⁵, hydroxyl, OR¹⁴, R⁶, and R²; R¹³ is independently selected fromthe group consisting of hydrogen, alkyl, alkenyl, alkynyl, —C(O)H,—C(O)alkyl, —C(S)alkyl, aryl, —SO₂alkyl, heteroaryl, arylalkyl, andheteroarylalkyl; or R¹³ is selected from the group consisting ofcycloalkyl, heterocycle, aryl, heteroaryl, arylalkyl, andheteroarylalkyl, each of which is optionally substituted with one ormore substituents selected from the group consisting of amino, —NHR¹⁴,—NR¹⁴R¹⁵, hydroxyl, OR¹⁴, R⁶, and R²; and R¹⁴ and R¹⁵ are independentlyselected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl,—C(O)H, —C(O)alkyl, —C(S)alkyl, aryl, —SO₂alkyl, heteroaryl, arylalkyl,and heteroarylalkyl.
 2. The compound of claim 1, wherein y is
 0. 3. Thecompound of claim 1, wherein y is
 1. 4. The compound of claim 1, whereiny is
 2. 5. The compound of claim 4, wherein two R¹ groups on adjacentring atoms or on the same ring atom together with the ring atom(s) towhich they are attached optionally form a 3-8-membered cycle.
 6. Thecompound of claim 5, wherein the 3-8-membered cycle is a 6-memberedcycle.
 7. The compound of claim 6, wherein R² is:


8. The compound of claim 1, wherein R² is heterocyclo optionallyindependently substituted with one or more R^(x) groups as allowed byvalance.
 9. The compound of claim 8, wherein R^(x) at each occurrence isindependently selected from the group consisting of halo, cyano, nitro,oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl,heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, andheterocycloalkyl.
 10. The compound of claim 1 wherein R² is:


11. The compound of claim 1, wherein m is
 0. 12. The compound of claim1, wherein n is
 0. 13. The compound of claim 1, wherein R³ and R⁴ arehydrogen.
 14. The compound of claim 1, wherein R⁵ is alkyl.
 15. Thecompound of claim 1, wherein R⁷ is


16. The compound of claim 15, wherein R² is heterocyclo optionallyindependently substituted with one or more R^(x) groups as allowed byvalance.
 17. The compound of claim 16, wherein R^(x) at each occurrenceis independently selected from the group consisting of halo, cyano,nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo,aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, andheterocycloalkyl.
 18. The compound of claim 1 selected from the groupconsisting of:

or a pharmaceutically acceptable salt thereof.
 19. A pharmaceuticalcomposition comprising an effective amount of a compound of claim 1 anda pharmaceutically acceptable carrier.
 20. A method for the treatment ofabnormal cellular proliferation comprising administering an effectiveamount to a host in need thereof of a compound of claim 1, optionally ina pharmaceutically acceptable carrier.